Combination therapy involving diaryl macrocyclic compounds

ABSTRACT

The present disclosure relates to methods and compositions for treating cancer with a diaryl macrocycle in combination with an inhibitor of MAPK/ERK kinase-1 and -2 (MEK1 and MEK2; MAP2K1 and MAP2K2), such as trametinib.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/941,031, filed Nov. 27, 2019; U.S. Provisional Application No.62/941,033, filed Nov. 27, 2019; and U.S. Provisional Application No.62/992,573, filed Mar. 20, 2020, each of which is incorporated herein inits entirety for all purposes.

TECHNICAL FIELD

The present disclosure relates to methods and compositions for treatingcancer with a diaryl macrocycle in combination with an inhibitor ofMAPK/ERK kinase-1 and -2 (MEK1 and MEK2; MAP2K1 and MAP2K2), such astrametinib.

BACKGROUND

Kirsten Rat Sarcoma Viral Oncogene homolog KRAS is one of three RASprotein family members (N, H, and K-RAS) that are small membrane boundintracellular GTPase proteins. KRAS cycles between an inactive guanosinediphosphate (GDP)-bound state and an active guanosine triphosphate(GTP)-bound state. Active GTP-bound KRAS interacts with numerouseffectors to stimulate multiple signaling pathways (e.g. PI3K-AKT-MTOR,RAF-MEK-ERK) to affect a range of cellular processes (e.g. survival,proliferation, cytoskeletal organization).

KRAS is one of the most frequently mutated oncogenes across a broadspectrum of human cancers (18%, Catalogue of Somatic Mutations in Cancer(COSMIC) database v90), including non-small cell lung, colorectal,pancreatic, uterine, bladder, stomach, renal, breast, skin, prostate,acute myeloid leukemia, cervical, liver acute lymphoblastic leukemia,ovarian, and brain cancers. KRAS mutations primarily occur in KRAScodons 12 and 13 but occur in codons 18, 61, 117, and 146 at lowfrequencies and have distinct effects on tumor cell signaling based onthe codon and missense mutation (Stolze et al. Sci Rep. 2015; 5:8535).

Direct targeting of a MEK1 and MEK2 through a reversible binding in anallosteric binding pocket has been evaluated in clinical trials withinvestigational drugs in patients harboring KRAS mutations. In a Phase 3clinical trial of the MEK inhibitor selumetinib in combination withdocetaxel in mutant KRAS NSCLC patients, there was no benefit of thecombination over docetaxel alone (Janne at al, 2017 JAMA). In a Phase 2clinical trial comparing trametinib treatment to docetaxel in patientswith mutant KRAS NSCLC was prematurely terminated because trametinibtreatment response crossed the futility boundary in the interim analysis(Blumenschein et al 2015). Single agent MEK drug clinical trials anddrug combinations of a MEK drug with chemotherapy has been shown to beineffective in mutant KRAS NSCLC.

Combinations that target MAPK pathway feedback re-activation,RTK-induced PI3K pathway activation and increased apoptosis will benecessary to provide significant improvements in clinical benefit.

SRC kinase has been identified to contribute broadly to cancer treatmentresistance including radiotherapy, chemotherapy, and targeted therapy(Zhang S and Yu D. Trends Pharmacol Sci. 2012; 33(3):122-8). SRC familykinases can promote mitogenic signaling from growth factor receptors ina number of ways, including initiation of signaling pathways requiredfor DNA synthesis, control of receptor turnover, actin cytoskeletonrearrangements and motility, and survival (Bromann et al, Oncogene 2004;23(48):7957-68). It was reported that KRAS induces a Src/PEAK1/ErbB2kinase amplification loop that drives metastatic growth and therapyresistance in pancreatic cancer (Kelber et al, Cancer Res. 2012;72(10):2554-64). The SRC inhibitor dasatinib was discovered to enhancethe anti-tumor activity of MEK inhibitor through inhibition of TAZactivity and the combination of dasatinib and trametinib represents apotential strategy for the treatment of KRAS-driven cancers (Rao et al,Eur J Cancer. 2018 August; 99:37-48). FAK plays a vital role insignaling pathways mediated through integrins, RTKs, RAS, and TGF β(Kanteti et al, Oncotarget. 2016; 7(21):31586-601) and is also likely tosuppress p53 expression to promote cell survival (Golubovskaya et al,International Review of Cytology. 2007; 263:103-153). Recent findingshave demonstrated that integrins participate in the regulation of cancerstem-cell biology and are required for cancer progression, metastasis,and drug resistance via SRC/FAK signaling (Seguin et al, Trends CellBiol. 2015; 25(4):234-40). Src has been identified as a key mediator ofthyroid cancer pro-tumorigenic processes and a promising therapeutictarget for thyroid cancer. However, single-agent Src inhibition promotesa more invasive phenotype through an IL-1β>FAK>p130Cas>c-Jun>MMPsignaling axis, and the combined inhibition of FAK and Src has thepotential to block Src inhibitor-induced phenotype switch and resistance(Kessler et al, Oncogene. 2019; 38:2565-2579). Compensatory upregulationof the PI3K/AKT signaling pathway is a resistance mechanism in targetingKRAS mutation, which promotes cancer cell survival. FAK throughphosphorylated Y397 directly interacts with the SH2 domain of p85, theregulatory subunit of PI3K to activate the PI3K pathway and suppressdoxorubicin-induced apoptosis (van Nimwegen et al, Mol Pharmacol. 2006;70(4):1330-1339). Src mediated phosphorylation of FAK at Y925 creates adocking site for GRB2 which activates the small GTP protein RAS and thedownstream ERK2 (MAPK) (Kanteti et al, Oncotarget. 2016;7(21):31586-601). Paxillin is a major component of focal adhesions thatform a structural link between extracellular matrix and actincytoskeleton. In cancer cells, its function is regulated through Src andFAK mediated phosphorylation. The dual inhibition of FAK and Srcinhibitor was much more effective as compared to FAK inhibition alone asevidenced with increased cell detachment, inhibition of AKT/ERK1/2 andSrc, and increased apoptosis (Golubovskaya et al, Molecular CancerResearch. 2003; 1(10):755-764). RhoA-FAK is a required signaling axisfor the maintenance of KRAS-driven lung adenocarcinomas. Pharmacologicinhibition of FAK in vivo downregulates p-AKT and does not trigger theemergence of PI3K/AKT-dependent compensatory mechanisms (Konstantinidouet al, Cancer Discov. 2013, 3(4):444-57). It was reported thatinterferon- and inflammatory-related gene sets were enriched in KRASmutant colon cell lines exhibiting intrinsic and acquired resistance toMEK inhibition (Wagner et al, Oncogene. 2019, 38(10):1717-1733). JAK2serves signal transduction for inflammatory cytokines and inhibition ofJAK2 may reduce the secretion of interferon- and inflammatory-relatedgene sets and sensitize KRAS mutant cell lines to MEK inhibition. Inpreclinical studies, MEK inhibition led to autocrine activation of STAT3through JAK and FGFR kinase activities to enable drug resistance (Lee etal, Cancer Cell 2014). The combination of the MEK inhibitor cobimetinibwith the JAK1/2 inhibitor ruxolitinib and multi-targeted kinaseinhibitor ponatinib (includes FGFR inhibitory activity) exhibitedenhanced efficacy in mouse xenograft tumor models (Lee et al, CancerCell 2014).

Overall, pharmacological targeting of central downstream signalingeffectors of mutant activated RAS proteins has been challenging and hasnot yet led to successful treatments in the clinic. The combination of aSRC/FAK/JAK2 inhibitor with a MEK1/2 inhibitor, in particulartrametinib, represents a novel therapeutic invention to maximize theantitumor activities and duration of response of a MEK1/2 inhibitor, inparticular trametinib, for the treatment of patients with KRAS mutation.

SUMMARY

It has been discovered that the combination of a MEK inhibitor, such astrametinib, and one or more compounds that inhibit FAK, SRC and/or JAK2provides a robust response in cancers driven by KRAS, in particular,cancers harboring one or more KRAS mutations.

In one aspect, the disclosure provides a method for treating cancer in ahost animal, the method comprising the step of administering to the hostanimal a therapeutically effective amount of one or more compounds thatinhibit FAK, SRC and/or JAK2, in combination with a therapeuticallyeffective amount of a MEK inhibitor, such as trametinib. In someembodiments, the host animal is a human patient. In some embodiments,the host animal is a laboratory animal such as a rodent.

In another aspect, the disclosure provides a method for treating cancerin a host animal, the method comprising the step of administering to thehost animal a therapeutically effective amount of a compound thatinhibits FAK, SRC, and JAK2, in combination with a therapeuticallyeffective amount of a MEK inhibitor, such as trametinib. In someembodiments, the host animal is a human patient. In some embodiments,the host animal is a laboratory animal such as a rodent.

In another aspect, the disclosure provides one of more compounds thatinhibit FAK, SRC and/or JAK2, or a pharmaceutically acceptable saltthereof, for use in the treatment of cancer in a patient, in combinationwith a therapeutically effective amount of a MEK inhibitor, such astrametinib.

In another aspect, the disclosure provides a compound that inhibits FAK,SRC and JAK2, or a pharmaceutically acceptable salt thereof, for use inthe treatment of cancer in a patient, in combination with atherapeutically effective amount of a MEK inhibitor, such as trametinib.

In another aspect, the disclosure provides use of one or more compoundsthat inhibit FAK, SRC and/or JAK2, or a pharmaceutically acceptable saltthereof, in the preparation of a medicament comprising a therapeuticallyeffective amount of the compound, for treating cancer in a patient incombination with a therapeutically effective amount of a MEK inhibitor,such as trametinib.

In another aspect, the disclosure provides use of a compound thatinhibits FAK, SRC and JAK2, or a pharmaceutically acceptable saltthereof, in the preparation of a medicament comprising a therapeuticallyeffective amount of the compound, for treating cancer in a patient incombination with a therapeutically effective amount of a MEK inhibitor,such as trametinib.

In another aspect, the disclosure provides a composition comprising oneor more compounds that inhibit FAK, SRC and/or JAK2, or apharmaceutically acceptable salt thereof, in a therapeutically effectiveamount, for use in the treatment of cancer in a patient, in combinationwith a therapeutically effective amount of a MEK inhibitor, such astrametinib.

In another aspect, the disclosure provides a composition comprising acompound that inhibits FAK, SRC and JAK2, or a pharmaceuticallyacceptable salt thereof, in a therapeutically effective amount, for usein the treatment of cancer in a patient, in combination with atherapeutically effective amount of a MEK inhibitor, such as trametinib.

In another aspect, the disclosure provides a medicament comprising oneor more compounds that inhibit FAK, SRC and/or JAK2, or apharmaceutically acceptable salt thereof, combined with a MEK inhibitor,such as trametinib, or a pharmaceutically acceptable salt thereof, infixed or free combination.

In another aspect, the disclosure provides a medicament comprising acompound that inhibits FAK, SRC and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a MEK inhibitor, such astrametinib, or a pharmaceutically acceptable salt thereof, in fixed orfree combination.

In another aspect, the disclosure provides a synergistic composition ofone or more compounds that inhibit FAK, SRC and/or JAK2 and a MEKinhibitor, such as trametinib, where the two components come intocontact with each other at a locus.

In another aspect, the disclosure provides a synergistic composition ofa compound that inhibits FAK, SRC and JAK2 and a MEK inhibitor, such astrametinib, where the two components come into contact with each otherat a locus.

In another aspect, the disclosure provides a synergistic composition ofone or more compounds that inhibit FAK, SRC and/or JAK2, and a MEKinhibitor, such as trametinib, where the two components come intocontact with each other only in the human body.

In another aspect, the disclosure provides a synergistic composition ofa compound that inhibits FAK, SRC and JAK2, and a MEK inhibitor, such astrametinib, where the two components come into contact with each otheronly in the human body.

In some embodiments the compound that inhibits FAK, SRC and JAK2 is ofthe formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

In some embodiments of the above aspects, the compound that inhibitsFAK, SRC and JAK2 is of the formula (referred to herein as Compound 1)

or a pharmaceutically acceptable salt thereof.

In some embodiments of the various aspects described herein, and inparticular those aspects described above, the cancer is non-small celllung cancer mediated by a genetically altered KRAS comprising at leastone mutation selected from the group consisting of G12C, G12V, G12D,G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L,and Q61R; or selected from the group consisting of G12D, G13D, and Q61H;or the KRAS comprises at least one mutation that is not G12A, G12C,G12S, G12V, and Q61K.

In some embodiments of the various aspects described herein, and inparticular those aspects described above, the cancer is colorectalcancer mediated by a genetically altered KRAS comprising at least onemutation selected from the group consisting of G12D, G12V, G13D, A146T,G12C, G12A, G12S, K117N, Q61K, G12R, M72V, S17G, K5R, D69G, G13C, G13R,Q61H, K117E, Q61L, Q61R, K117R, A146V, A146P, K147N, and R97I.

In some embodiments of the various aspects described herein, and inparticular those aspects described above, the cancer is pancreaticcancer mediated by a genetically altered KRAS comprising at least onemutation selected from the group consisting of G12D, G12V, G12R, Q61H,G12C, and G12S.

Additional embodiments, features, and advantages of the disclosure willbe apparent from the following detailed description and through practiceof the disclosure. The compounds of the present disclosure can bedescribed as embodiments in any of the following enumerated clauses. Itwill be understood that any of the embodiments described herein can beused in connection with any other embodiments described herein to theextent that the embodiments do not contradict one another.

1. A method of treating cancer in a patient in need of such treatment,the method comprising the step of administering to the patient atherapeutically effective amount of a compound that inhibits FAK, SRC,and JAK2, in combination with a therapeutically effective amount oftrametinib.

2. A method of treating cancer in patient in need of such treatment, themethod comprising the step of administering to the patient having cancera therapeutically effective amount of a compound that inhibits FAK, SRC,and JAK2, in combination with a therapeutically effective amount oftrametinib, wherein at least one genetically altered oncogenic gene hasbeen previously identified in the patient.

3. A method of treating a cancer mediated by at least one geneticallyaltered oncogenic gene, in patient in need of such treatment, the methodcomprising the step of administering to the patient having cancer atherapeutically effective amount of a compound that inhibits FAK, SRC,and JAK2, in combination with a therapeutically effective amount oftrametinib.

4. A method of treating cancer in a patient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        in the patient, and    -   ii. administering to the patient a therapeutically effective        amount of a compound that inhibits FAK, SRC, and JAK2, in        combination with a therapeutically effective amount of        trametinib.

5. The method of any one of clauses 2 to 4, wherein the at least onegenetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, and/or a genetically alteredPI3K.

6. A method of treating non-small cell lung cancer in patient in need ofsuch treatment, the method comprising the step of administering to thepatient having non-small cell lung cancer a therapeutically effectiveamount of a compound that inhibits FAK, SRC, and JAK2, in combinationwith a therapeutically effective amount of trametinib.

7. A method of treating non-small cell lung cancer in patient in need ofsuch treatment, the method comprising the step of administering to thepatient having cancer a therapeutically effective amount of a compoundthat inhibits FAK, SRC, and JAK2, in combination with a therapeuticallyeffective amount of trametinib, wherein at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K has beenpreviously identified in the patient.

8. A method of treating non-small cell lung cancer mediated by at leastone genetically altered oncogenic gene selected from a geneticallyaltered KRAS, a genetically altered NRAS, a genetically altered HRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K, in patient in need of such treatment, the methodcomprising the step of administering to the patient having non-smallcell lung cancer a therapeutically effective amount of a compound thatinhibits FAK, SRC, and JAK2, in combination with a therapeuticallyeffective amount of trametinib.

9. A method of treating non-small cell lung cancer in a patientcomprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of a compound that inhibits FAK, SRC, and JAK2, in        combination with a therapeutically effective amount of        trametinib.

10. The method of any one of clauses 7 to 9, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D,G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from the groupconsisting of G12D, G13D, and Q61H; or KRAS comprises at least onemutation that is not G12A, G12C, G12S, G12V, and Q61K.

11. A method for treating colorectal cancer or pancreatic cancer in apatient in need of such treatment, the method comprising the step ofadministering to the patient a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, in combination with atherapeutically effective amount of trametinib.

12. A method of treating colorectal cancer or pancreatic cancer inpatient in need of such treatment, the method comprising the step ofadministering to the patient having cancer a therapeutically effectiveamount of a compound that inhibits FAK, SRC, and JAK2, in combinationwith a therapeutically effective amount of trametinib, wherein at leastone genetically altered oncogenic gene selected from a geneticallyaltered KRAS, a genetically altered NRAS, a genetically altered HRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K has been previously identified in the patient.

13. A method of treating colorectal cancer or pancreatic cancer mediatedby at least one genetically altered oncogenic gene selected from agenetically altered KRAS, a genetically altered NRAS, a geneticallyaltered HRAS, a genetically altered BRAF, a genetically altered MEK, ora genetically altered PI3K, in patient in need of such treatment, themethod comprising the step of administering to the patient havingcolorectal cancer or pancreatic cancer a therapeutically effectiveamount of a compound that inhibits FAK, SRC, and JAK2, in combinationwith a therapeutically effective amount of trametinib.

14. A method of treating colorectal cancer or pancreatic cancer in apatient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of a compound that inhibits FAK, SRC, and JAK2, in        combination with a therapeutically effective amount of        trametinib.

15. The method of any one of clauses 12 to 14, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K,G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R,A146V, A146P, K147N, and R97I; or selected from the group consisting ofG12D, G12V, G12R, Q61H, G12C, and G12S.

16. The method of any one of the preceding clauses, wherein the compoundthat inhibits FAK, SRC, and JAK2 is administered in an amount of fromabout 40 mg to about 200 mg.

17. The method of any one of the preceding clauses, wherein trametinibis administered in an amount of from about 0.5 mg to about 2.5 mg.

18. The method of any one of the preceding clauses, wherein the compoundthat inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

19. The method of any one of the preceding clauses, wherein the compoundthat inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

20. The method according to any one of the preceding clauses, whereinthe compound that inhibits FAK, SRC and JAK2 is administered in anamount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg byonce a day or twice a day.

21. The method according to any one of the preceding clauses, whereintrametinib is administered in an amount of about 1 mg or about 2 mg.

22. The method according to any one of the preceding clauses, whereinthe compound that inhibits FAK, SRC and JAK2 is administered on aschedule of at least one dose of about 40 mg, about 80 mg QD, about 120mg QD, or about 160 mg QD, followed by at least one dose of about 40 mgBID, about 80 mg BID, about 120 mg BID, or about 160 mg BID.

23. The method according to any one of the preceding clauses, whereintrametinib is administered in at least one dose of about 1 mg QD, orabout 2 mg QD.

24. The method according to any one of the preceding clauses, whereinthe compound that inhibits FAK, SRC and JAK2 is administered at the sametime as trametinib.

25. The method according to any one of clauses 1 to 23, wherein thecompound that inhibits FAK, SRC and JAK2 is administered prior totrametinib.

26. The method according to any one of clauses 1 to 23, wherein thecompound that inhibits FAK, SRC and JAK2 is administered aftertrametinib.

27. The method according to any one of the preceding clauses, whereinthe patient has not received a prior treatment.

28. The method according to any one of clauses 1 to 26, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies.

29. The method according to any one of clauses 1 to 26 or 28, whereinthe patient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

30. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating cancer in apatient in need of such treatment.

31. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating cancer in patientin need of such treatment, wherein at least one genetically alteredoncogenic gene has been previously identified in the patient, the methodcomprising the step of administering to the patient a therapeuticallyeffective amount of the compound that inhibits FAK, SRC, and JAK2 incombination with trametinib.

32. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating a cancer mediatedby at least one genetically altered oncogenic gene, in patient in needof such treatment, the method comprising the step of administering tothe patient a therapeutically effective amount of the compound thatinhibits FAK, SRC, and JAK2 in combination with trametinib.

33. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating cancer in apatient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        in the patient, and    -   ii. administering to the patient a therapeutically effective        amount of the compound that inhibits FAK, SRC, and JAK2, in        combination with trametinib.

34. The compound of any one of clauses 31 to 33, wherein the at leastone genetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, and/or a genetically alteredPI3K.

35. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating non-small celllung cancer in patient in need of such treatment, the method comprisingthe step of administering to the patient a therapeutically effectiveamount of the compound that inhibits FAK, SRC, and JAK2 in combinationwith trametinib.

36. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating non-small celllung cancer in patient in need of such treatment, the method comprisingthe step of administering to the patient a therapeutically effectiveamount of a compound that inhibits FAK, SRC, and JAK2 in combinationwith trametinib, wherein at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K has been previouslyidentified in the patient.

37. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating non-small celllung cancer mediated by at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K, in patient in need of suchtreatment, the method comprising the step of administering to thepatient a therapeutically effective amount of a compound that inhibitsFAK, SRC, and JAK2 in combination with trametinib.

38. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating non-small celllung cancer in a patient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of the compound that inhibits FAK, SRC, and JAK2 in        combination with trametinib.

39. The compound of any one of clauses 36 to 38, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D,G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from the groupconsisting of G12D, G13D, and Q61H; or KRAS comprises at least onemutation that is not G12A, G12C, G12S, G12V, and Q61K.

40. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method for treating colorectal canceror pancreatic cancer in a patient in need of such treatment, the methodcomprising the step of administering to the patient a therapeuticallyeffective amount of the compound that inhibits FAK, SRC, and JAK2 incombination with trametinib.

41. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating colorectal canceror pancreatic cancer in patient in need of such treatment, the methodcomprising the step of administering to the patient a therapeuticallyeffective amount of the compound that inhibits FAK, SRC, and JAK2 incombination with trametinib, wherein at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K has beenpreviously identified in the patient.

42. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating colorectal canceror pancreatic cancer mediated by at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K, in patient inneed of such treatment, the method comprising the step of administeringto the patient a therapeutically effective amount of a compound thatinhibits FAK, SRC, and JAK2 in combination with trametinib.

43. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of trametinib, for use in a method of treating colorectal canceror pancreatic cancer in a patient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of the compound that inhibits FAK, SRC, and JAK2 in        combination with trametinib.

44. The compound of any one of clauses 41 to 43, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K,G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R,A146V, A146P, K147N, and R97I; or selected from the group consisting ofG12D, G12V, G12R, Q61H, G12C, and G12S.

45. The compound of any one of clauses 30 to 44, wherein the compoundthat inhibits FAK, SRC, and JAK2 is administered in an amount of fromabout 40 mg to about 200 mg.

46. The compound of any one of clauses 30 to 45, wherein trametinib isadministered in an amount of from about 0.5 mg to about 2.5 mg.

47. The compound of any one of clauses 30 to 46, wherein the compoundthat inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

48. The compound of any one of clauses 30 to 47, wherein the compoundthat inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

49. The compound of any one of clauses 30 to 48, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered in an amount of about 40mg, about 80 mg, about 120 mg, or about 160 mg.

50. The compound of any one of clauses 30 to 49, wherein trametinib isadministered in an amount of about 1 mg or about 2 mg.

51. The compound of any one of clauses 30 to 50, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered on a schedule of atleast one dose of about 40 mg, about 80 mg QD, about 120 mg QD, or about160 mg QD, followed by at least one dose of about 40 mg BID, about 80 mgBID, about 120 mg BID, or about 160 mg BID.

52. The compound of any one of clauses 30 to 51, wherein trametinib isadministered in at least one dose of about 1 mg QD, or about 2 mg QD.

53. The compound of any one of clauses 30 to 52, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered at the same time astrametinib.

54. The compound of any one of clauses 30 to 52, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered prior to trametinib.

55. The compound of any one of clauses 30 to 52, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered after trametinib.

56. The compound of any one of clauses 30 to 55, wherein the patient hasnot received a prior treatment.

57. The compound of any one of clauses 30 to 55, wherein the patient hasreceived at least one prior treatment of one or more chemotherapeuticagents or immunotherapies.

58. The compound of any one of clauses 30 to 55 or 57, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

59. Use of a compound that inhibits FAK, SRC and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating cancer in a patient incombination with a therapeutically effective amount of trametinib.

60. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating cancer in a patient incombination with a therapeutically effective amount of trametinib,wherein at least one genetically altered oncogenic gene has beenpreviously identified in the patient.

61. Use of compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating a cancer in a patient incombination with a therapeutically effective amount of trametinib,wherein the cancer is mediated by at least one genetically alteredoncogenic gene.

62. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for use in a method of treating acancer in a patient in combination with a therapeutically effectiveamount of trametinib, wherein the method comprises;

-   -   i. identifying at least one genetically altered oncogenic gene        in the patient, and    -   ii. administering to the patient the medicament in combination        with trametinib.

63. The use of any one of clauses 31 to 33, wherein the at least onegenetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, and/or a genetically alteredPI3K.

64. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating non-small cell lungcancer in a patient in combination with a therapeutically effectiveamount of trametinib.

65. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating non-small cell lungcancer in a patient in combination with a therapeutically effectiveamount of trametinib, wherein at least one genetically altered oncogenicgene selected from a genetically altered KRAS, a genetically alteredNRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K has beenpreviously identified in the patient.

66. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating non-small cell lungcancer mediated by at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS,genetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K in a patient in combinationwith a therapeutically effective amount of trametinib.

67. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for use in a method of treatingnon-small cell lung cancer in a patient in combination with atherapeutically effective amount of trametinib, the method comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient the medicament in combination        with trametinib.

68. The use of any one of clauses 65 to 67, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D,G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from the groupconsisting of G12D, G13D, and Q61H; or KRAS comprises at least onemutation that is not G12A, G12C, G12S, G12V, and Q61K.

69. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating colorectal cancer orpancreatic cancer in a patient in combination with a therapeuticallyeffective amount of trametinib.

70. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating colorectal cancer orpancreatic cancer in a patient in combination with a therapeuticallyeffective amount of trametinib, wherein at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K has beenpreviously identified in the patient.

71. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating colorectal cancer orpancreatic cancer mediated by at least one genetically altered oncogenicgene selected from a genetically altered KRAS, a genetically alteredNRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K in a patient incombination with a therapeutically effective amount of trametinib.

72. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for use in a method of treatingcolorectal cancer or pancreatic cancer in a patient in combination witha therapeutically effective amount of trametinib, the method comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient the medicament in combination        with trametinib.

73. The use of any one of clauses 70 to 72, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K,G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R,A146V, A146P, K147N, and R97I; or selected from the group consisting ofG12D, G12V, G12R, Q61H, G12C, and G12S.

74. The use of any one of clauses 59 to 73, wherein the compound thatinhibits FAK, SRC, and JAK2 is administered in an amount of from about40 mg to about 200 mg.

75. The use of any one of clauses 59 to 74, wherein trametinib isadministered in an amount of from about 0.5 mg to about 2.5 mg.

76. The use of any one of clauses 59 to 75, wherein the compound thatinhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

77. The use of any one of clauses 59 to 76, wherein the compound thatinhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

78. The use of any one of clauses 59 to 77, wherein the compound thatinhibits FAK, SRC and JAK2 is administered in an amount of about 40 mg,about 80 mg, about 120 mg, or about 160 mg.

79. The use of any one of clauses 59 to 78, wherein trametinib isadministered in an amount of about 1 mg or about 2 mg.

80. The use of any one of clauses 59 to 79, wherein the compound thatinhibits FAK, SRC and JAK2 is administered on a schedule of at least onedose of about 40 mg QD. about 80 mg QD, about 120 mg QD, or about 160 mgQD, followed by at least one dose of about 40 mg BID, about 80 mg BID,about 120 mg BID, or about 160 mg BID.

81. The use of any one of clauses 59 to 80, wherein trametinib isadministered in at least one dose of about 1 mg QD, or about 2 mg QD.

82. The use of any one of clauses 59 to 81, wherein the compound thatinhibits FAK, SRC and JAK2 is administered at the same time astrametinib.

83. The use of any one of clauses 59 to 81, wherein the compound thatinhibits FAK, SRC and JAK2 is administered prior to trametinib.

84. The use of any one of clauses 59 to 81, wherein the compound thatinhibits FAK, SRC and JAK2 is administered after trametinib.

85. The use of any one of clauses 59 to 84, wherein the patient has notreceived a prior treatment.

86. The use of any one of clauses 59 to 84, wherein the patient hasreceived at least one prior treatment of one or more chemotherapeuticagents or immunotherapies.

87. The use of any one of clauses 59 to 84 or 86, wherein the patienthas received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

88. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination.

89. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect on a cancer in a patient,wherein at least one genetically altered oncogenic gene has beenpreviously identified in the patient.

90. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect on a cancer mediated by atleast one genetically altered oncogenic gene.

91. The medicament of clause 89 or 90, wherein the at least onegenetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered BRAF, a geneticallyaltered MEK, and/or a genetically altered PI3K.

92. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect for treating non-small celllung cancer.

93. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect for treating non-small celllung cancer in a patient, wherein at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered BRAF, a genetically altered MEK, ora genetically altered PI3K has been previously identified in thepatient.

94. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect for treating non-small celllung cancer mediated by at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K in a patient.

95. The medicament of clause 93 or 94, wherein the genetically alteredKRAS comprises at least one mutation selected from the group consistingof G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R,G13E, Q61H, Q61E, Q61L, and Q61R, or selected from the group consistingof G12D, G13D, and Q61H; or KRAS comprises at least one mutation that isnot G12A, G12C, G12S, G12V, and Q61K.

96. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect for treating colorectal canceror pancreatic cancer in a patient.

97. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect for treating colorectal canceror pancreatic cancer in a patient, wherein at least one geneticallyaltered oncogenic gene selected from a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, or a genetically altered PI3Khas been previously identified in the patient.

98. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of trametinib, in fixed or free combination, wherein themedicament provides a synergistic effect for treating colorectal canceror pancreatic cancer mediated by at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K in a patient.

99. The medicament of clause 97 or 98, wherein the genetically alteredKRAS comprises at least one mutation selected from the group consistingof G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K, G12R, M72V,S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R, A146V,A146P, K147N, and R97I; or selected from the group consisting of G12D,G12V, G12R, Q61H, G12C, and G12S.

100. The medicament of any one of clauses 88 to 99, wherein the compoundthat inhibits FAK, SRC, and JAK2 is provided in the medicament in anamount of from about 40 mg to about 200 mg.

101. The medicament of any one of clauses 88 to 100, wherein trametinibis provided in the medicament in an amount of from about 0.5 mg to about2.5 mg.

102. The medicament of any one of clauses 88 to 101, wherein thecompound that inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

103. The medicament of any one of clauses 88 to 102, wherein thecompound that inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

104. The medicament of any one of clauses 88 to 103, wherein thecompound that inhibits FAK, SRC and JAK2 is provided in the medicamentin an amount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg.

105. The medicament of any one of clauses 88 to 104, wherein trametinibis provided in the medicament in an amount of about 1 mg or about 2 mg.

106. The medicament of any one of clauses 88 to 105, wherein thecompound that inhibits FAK, SRC and JAK2 is provided in the medicamenton a schedule of at least one dose of about 40 mg QD, about 80 mg QD,about 120 mg QD, or about 160 mg QD, followed by at least one dose ofabout 40 mg BID, about 80 mg BID, about 120 mg BID, or about 160 mg BID.

107. The medicament of any one of clauses 88 to 106, wherein trametinibis provided in the medicament for administration in at least one dose ofabout 1 mg QD, or about 2 mg QD.

108. The medicament of any one of clauses 88 to 107, wherein thecompound that inhibits FAK, SRC and JAK2 is provided at the same time astrametinib.

109. The medicament of any one of clauses 88 to 107, in freecombination, wherein the compound that inhibits FAK, SRC and JAK2 isprovided prior to trametinib.

110. The medicament of any one of clauses 88 to 107, in freecombination, wherein the compound that inhibits FAK, SRC and JAK2 isprovided after trametinib.

111. The medicament of any one of clauses 88 to 110, wherein the patienthas not received a prior treatment.

112. The medicament of any one of clauses 88 to 110, wherein the patienthas received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies.

113. The medicament of any one of clauses 88 to 110 or 112, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

114. A synergistic composition of a compound that inhibits FAK, SRC andJAK2 and trametinib, where the two components come into contact witheach other at a locus.

115. The synergistic composition of clause 114, wherein the compoundthat inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

116. The synergistic composition of clause 114 or 115, wherein thecompound that inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

117. The synergistic composition of any one of clauses 114 to 116,wherein the locus is a cancer or a cancer cell.

118. The synergistic composition of any one of clauses 114 to 117,wherein the locus is a cancer selected from non-small cell lung cancer,colorectal cancer or pancreatic cancer and pancreatic cancer.

119. The synergistic composition of clause 118, wherein the cancer isnon-small cell lung cancer.

120. The synergistic composition of clause 118, wherein the cancer iscolorectal cancer or pancreatic cancer.

121. The synergistic composition of any one of clauses 114 to 120,wherein the locus comprises at least one genetically altered oncogenicgene selected from a genetically altered KRAS, a genetically alteredNRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K.

122. The synergistic composition of any one of clauses 114 to 121,wherein the locus comprises a genetically altered KRAS having at leastone mutation selected from the group consisting of G12C, G12V, G12D,G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L,and Q61R; or selected from the group consisting of G12A, G12C, G12D,G12S, G12V, G13D, Q61H, and Q61K, or selected from the group consistingof G12D, G13D, and Q61H; or selected from the group consisting of G12D,G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K, G12R, M72V, S17G, K5R,D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R, A146V, A146P, K147N,and R97I; or selected from the group consisting of G12D, G12V, G12R,Q61H, G12C, and G12S; or KRAS comprises at least one mutation that isnot G12A, G12C, G12S, G12V, and Q61K.

123. The synergistic composition of any one of clauses 114 to 122,wherein the compound that inhibits FAK, SRC, and JAK2 is provided in thecomposition in an amount of from about 40 mg to about 200 mg.

124. The synergistic composition of any one of clauses 114 to 123,wherein trametinib is provided in the composition in an amount of fromabout 0.5 mg to about 2.5 mg.

125. The synergistic composition of any one of clauses 114 to 124,wherein the compound that inhibits FAK, SRC and JAK2 is provided in thecomposition in an amount of about 40 mg, about 80 mg, about 120 mg, orabout 160 mg.

126. The synergistic composition of any one of clauses 114 to 125,wherein trametinib is provided in the composition in an amount of about1 mg or about 2 mg.

127. A synergistic composition of a compound that inhibits FAK, SRC andJAK2 and trametinib, where the two components come into contact witheach other only in the human body.

128. The synergistic composition of clause 127, wherein the compoundthat inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

129. The synergistic composition of clause 127 or 128, wherein thecompound that inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

130. The synergistic composition of any one of clauses 127 to 129,wherein the human body comprises at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered BRAF, a genetically altered MEK, ora genetically altered PI3K.

131. The synergistic composition of any one of clauses 127 to 130,wherein the human body comprises a genetically altered KRAS having atleast one mutation selected from the group consisting of G12C, G12V,G12D, G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R, G13E, Q61H, Q61E,Q61L, and Q61R; or selected from the group consisting of G12A, G12C,G12D, G12S, G12V, G13D, Q61H, and Q61K, or selected from the groupconsisting of G12D, G13D, and Q61H; or selected from the groupconsisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K,G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R,A146V, A146P, K147N, and R97I; or selected from the group consisting ofG12D, G12V, G12R, Q61H, G12C, and G12S; or KRAS comprises at least onemutation that is not G12A, G12C, G12S, G12V, and Q61K.

132. The synergistic composition of any one of clauses 127 to 131,wherein the compound that inhibits FAK, SRC, and JAK2 is provided in thecomposition in an amount of from about 40 mg to about 200 mg.

133. The synergistic composition of any one of clauses 127 to 132,wherein trametinib is provided in the composition in an amount of fromabout 0.5 mg to about 2.5 mg.

134. The synergistic composition of any one of clauses 127 to 133,wherein the compound that inhibits FAK, SRC and JAK2 is provided in thecomposition in an amount of about 40 mg, about 80 mg, about 120 mg, orabout 160 mg.

135. The synergistic composition of any one of clauses 127 to 134,wherein trametinib is provided in the composition in an amount of about1 mg or about 2 mg.

136. The synergistic composition of any one of clauses 127 to 135,wherein the human body has not received a prior treatment.

137. The synergistic composition of any one of clauses 127 to 135,wherein the human body has received at least one prior treatment of oneor more chemotherapeutic agents or immunotherapies.

138. The synergistic composition of any one of clauses 127 to 135 or137, wherein the host animal is a human patient in need of suchtreatment who has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and developed an acquiredresistance to the treatment or developed bypass resistance to thetreatment.

139. A method of treating cancer in a patient in need of such treatment,the method comprising the step of administering to the patient atherapeutically effective amount of a compound that inhibits FAK, SRC,and JAK2, in combination with a therapeutically effective amount of aMEK inhibitor, provided that the MEK inhibitor is not trametinib.

140. A method of treating cancer in patient in need of such treatment,the method comprising the step of administering to the patient havingcancer a therapeutically effective amount of a compound that inhibitsFAK, SRC, and JAK2, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, wherein at least one genetically altered oncogenic gene hasbeen previously identified in the patient.

141. A method of treating a cancer mediated by at least one geneticallyaltered oncogenic gene, in patient in need of such treatment, the methodcomprising the step of administering to the patient having cancer atherapeutically effective amount of a compound that inhibits FAK, SRC,and JAK2, in combination with a therapeutically effective amount of aMEK inhibitor, provided that the MEK inhibitor is not trametinib.

142. A method of treating cancer in a patient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        in the patient, and    -   ii. administering to the patient a therapeutically effective        amount of a compound that inhibits FAK, SRC, and JAK2, in        combination with a therapeutically effective amount of a MEK        inhibitor, provided that the MEK inhibitor is not trametinib.

143. The method of any one of clauses 140 to 142, wherein the at leastone genetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, and/or a genetically alteredPI3K.

144. A method of treating non-small cell lung cancer in patient in needof such treatment, the method comprising the step of administering tothe patient having non-small cell lung cancer a therapeuticallyeffective amount of a compound that inhibits FAK, SRC, and JAK2, incombination with a therapeutically effective amount of a MEK inhibitor,provided that the MEK inhibitor is not trametinib.

145. A method of treating non-small cell lung cancer in patient in needof such treatment, the method comprising the step of administering tothe patient having cancer a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, in combination with atherapeutically effective amount of a MEK inhibitor, provided that theMEK inhibitor is not trametinib, wherein at least one geneticallyaltered oncogenic gene selected from a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, or a genetically altered PI3Khas been previously identified in the patient.

146. A method of treating non-small cell lung cancer mediated by atleast one genetically altered oncogenic gene selected from a geneticallyaltered KRAS, a genetically altered NRAS, a genetically altered HRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K, in patient in need of such treatment, the methodcomprising the step of administering to the patient having non-smallcell lung cancer a therapeutically effective amount of a compound thatinhibits FAK, SRC, and JAK2, in combination with a therapeuticallyeffective amount of a MEK inhibitor, provided that the MEK inhibitor isnot trametinib.

147. A method of treating non-small cell lung cancer in a patientcomprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of a compound that inhibits FAK, SRC, and JAK2, in        combination with a therapeutically effective amount of a MEK        inhibitor, provided that the MEK inhibitor is not trametinib.

148. The method of any one of clauses 145 to 147, wherein thegenetically altered KRAS comprises at least one mutation selected fromthe group consisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F,G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from thegroup consisting of G12D, G13D, and Q61H.

149. A method for treating colorectal cancer or pancreatic cancer in apatient in need of such treatment, the method comprising the step ofadministering to the patient a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, in combination with atherapeutically effective amount of a MEK inhibitor, provided that theMEK inhibitor is not trametinib.

150. A method of treating colorectal cancer or pancreatic cancer inpatient in need of such treatment, the method comprising the step ofadministering to the patient having cancer a therapeutically effectiveamount of a compound that inhibits FAK, SRC, and JAK2, in combinationwith a therapeutically effective amount of a MEK inhibitor, providedthat the MEK inhibitor is not trametinib, wherein at least onegenetically altered oncogenic gene selected from a genetically alteredKRAS, a genetically altered NRAS, a genetically altered HRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K has been previously identified in the patient.

151. A method of treating colorectal cancer or pancreatic cancermediated by at least one genetically altered oncogenic gene selectedfrom a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K, in patient in need of suchtreatment, the method comprising the step of administering to thepatient having colorectal cancer or pancreatic cancer a therapeuticallyeffective amount of a compound that inhibits FAK, SRC, and JAK2, incombination with a therapeutically effective amount of a MEK inhibitor,provided that the MEK inhibitor is not trametinib.

152. A method of treating colorectal cancer or pancreatic cancer in apatient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of a compound that inhibits FAK, SRC, and JAK2, in        combination with a therapeutically effective amount of a MEK        inhibitor, provided that the MEK inhibitor is not trametinib.

153. The method of any one of clauses 150 to 152, wherein thegenetically altered KRAS comprises at least one mutation selected fromthe group consisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S,K117N, Q61K, G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L,Q61R, K117R, A146V, A146P, K147N, and R97I; or selected from the groupconsisting of G12D, G12V, G12R, Q61H, G12C, and G12S.

154. The method of any one of the preceding clauses, wherein thecompound that inhibits FAK, SRC, and JAK2 is administered in an amountof from about 40 mg to about 200 mg.

155. The method of any one of the preceding clauses, wherein thecompound that inhibits FAK, SRC, and JAK2 is administered in an amountof about 40 mg, or about 80 mg, or about 120 mg, or about 160 mg.

156. The method of any one of the preceding clauses, wherein thecompound that inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, C(O)NH₂,C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, CO₂C₁C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

157. The method of any one of the preceding clauses, wherein thecompound that inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

158. The method according to any one of the preceding clauses, whereinthe compound that inhibits FAK, SRC and JAK2 is administered in anamount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg byonce a day or twice a day.

159. The method according to any one of the preceding clauses, whereinthe MEK inhibitor is pimasertib, selumetinib, cobimetinib, PD-0325901,refametinib, TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973,AZD8330, AZD6244, or CI-1040.

160. The method according to any one of the preceding clauses, whereinthe compound that inhibits FAK, SRC and JAK2 is administered on aschedule of at least one dose of about 40 mg, about 80 mg QD, about 120mg QD, or about 160 mg QD, followed by at least one dose of about 40 mgBID, about 80 mg BID, about 120 mg BID, or about 160 mg BID.

161. The method according to any one of the preceding clauses, whereinthe MEK inhibitor is selumetinib.

162. The method according to any one of the preceding clauses, whereinthe compound that inhibits FAK, SRC and JAK2 is administered at the sametime as the MEK inhibitor.

163. The method according to any one of clauses 139 to 161, wherein thecompound that inhibits FAK, SRC and JAK2 is administered prior to theMEK inhibitor.

164. The method according to any one of clauses 139 to 161, wherein thecompound that inhibits FAK, SRC and JAK2 is administered after the MEKinhibitor.

165. The method according to any one of the preceding clauses, whereinthe patient has not received a prior treatment.

166. The method according to any one of clauses 1 to 164, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies.

167. The method according to any one of clauses 1 to 164 or 166, whereinthe patient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

168. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating cancer in a patient in needof such treatment.

169. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating cancer in patient in need ofsuch treatment, wherein at least one genetically altered oncogenic genehas been previously identified in the patient, the method comprising thestep of administering to the patient a therapeutically effective amountof the compound that inhibits FAK, SRC, and JAK2 in combination with aMEK inhibitor, provided that the MEK inhibitor is not trametinib.

170. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating a cancer mediated by atleast one genetically altered oncogenic gene, in patient in need of suchtreatment, the method comprising the step of administering to thepatient a therapeutically effective amount of the compound that inhibitsFAK, SRC, and JAK2 in combination with a MEK inhibitor, provided thatthe MEK inhibitor is not trametinib.

171. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating cancer in a patientcomprising;

-   -   i. identifying at least one genetically altered oncogenic gene        in the patient, and    -   ii. administering to the patient a therapeutically effective        amount of the compound that inhibits FAK, SRC, and JAK2, in        combination with a MEK inhibitor, provided that the MEK        inhibitor is not trametinib.

172. The compound of any one of clauses 169 to 171, wherein the at leastone genetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, and/or a genetically alteredPI3K.

173. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating non-small cell lung cancerin patient in need of such treatment, the method comprising the step ofadministering to the patient a therapeutically effective amount of thecompound that inhibits FAK, SRC, and JAK2 in combination with a MEKinhibitor, provided that the MEK inhibitor is not trametinib.

174. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating non-small cell lung cancerin patient in need of such treatment, the method comprising the step ofadministering to the patient a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2 in combination with a MEKinhibitor, provided that the MEK inhibitor is not trametinib, wherein atleast one genetically altered oncogenic gene selected from a geneticallyaltered KRAS, a genetically altered NRAS, a genetically altered HRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K has been previously identified in the patient.

175. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating non-small cell lung cancermediated by at least one genetically altered oncogenic gene selectedfrom a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K, in patient in need of suchtreatment, the method comprising the step of administering to thepatient a therapeutically effective amount of a compound that inhibitsFAK, SRC, and JAK2 in combination with a MEK inhibitor, provided thatthe MEK inhibitor is not trametinib.

176. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating non-small cell lung cancerin a patient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of the compound that inhibits FAK, SRC, and JAK2 in        combination with a MEK inhibitor, provided that the Mek        inhibitor is not trametinib.

177. The compound of any one of clauses 174 to 176, wherein thegenetically altered KRAS comprises at least one mutation selected fromthe group consisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F,G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from thegroup consisting of G12D, G13D, and Q61H.

178. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method for treating colorectal cancer orpancreatic cancer in a patient in need of such treatment, the methodcomprising the step of administering to the patient a therapeuticallyeffective amount of the compound that inhibits FAK, SRC, and JAK2 incombination with a MEK inhibitor, provided that the MEK inhibitor is nottrametinib.

179. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating colorectal cancer orpancreatic cancer in patient in need of such treatment, the methodcomprising the step of administering to the patient a therapeuticallyeffective amount of the compound that inhibits FAK, SRC, and JAK2 incombination with a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, wherein at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K has been previouslyidentified in the patient.

180. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating colorectal cancer orpancreatic cancer mediated by at least one genetically altered oncogenicgene selected from a genetically altered KRAS, a genetically alteredNRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K, in patient inneed of such treatment, the method comprising the step of administeringto the patient a therapeutically effective amount of a compound thatinhibits FAK, SRC, and JAK2 in combination with a MEK inhibitor,provided that the MEK inhibitor is not trametinib.

181. A compound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, for use in a method of treating colorectal cancer orpancreatic cancer in a patient comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient a therapeutically effective        amount of the compound that inhibits FAK, SRC, and JAK2 in        combination with a MEK inhibitor, provided that the MEK        inhibitor is not trametinib.

182. The compound of any one of clauses 179 to 181, wherein thegenetically altered KRAS comprises at least one mutation selected fromthe group consisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S,K117N, Q61K, G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L,Q61R, K117R, A146V, A146P, K147N, and R97I; or selected from the groupconsisting of G12D, G12V, G12R, Q61H, G12C, and G12S.

183. The compound of any one of clauses 168 to 182, wherein the compoundthat inhibits FAK, SRC, and JAK2 is administered in an amount of fromabout 40 mg to about 200 mg.

184. The compound of any one of clauses 168 to 183, wherein the compoundthat inhibits FAK, SRC, and JAK2 is administered in an amount of about40 mg, or about 80 mg, or about 120 mg, or about 160 mg.

185. The compound of any one of clauses 168 to 184, wherein the compoundthat inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, C(O)NH₂,C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7 memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, CO₂C₁C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

186. The compound of any one of clauses 168 to 185, wherein the compoundthat inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

187. The compound of any one of clauses 168 to 186, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered in an amount of about 40mg, about 80 mg, about 120 mg, or about 160 mg.

188. The compound of any one of clauses 168 to 187, wherein the MEKinhibitor is pimasertib, selumetinib, cobimetinib, PD-0325901,refametinib, TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973,AZD8330, AZD6244, or CI-1040.

189. The compound of any one of clauses 168 to 188, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered on a schedule of atleast one dose of about 40 mg, about 80 mg QD, about 120 mg QD, or about160 mg QD, followed by at least one dose of about 40 mg BID, about 80 mgBID, about 120 mg BID, or about 160 mg BID.

190. The compound of any one of clauses 168 to 189, wherein the MEKinhibitor is selumetinib.

192. The compound of any one of clauses 168 to 190, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered at the same time as theMEK inhibitor.

193. The compound of any one of clauses 168 to 190, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered prior to the MEKinhibitor.

194. The compound of any one of clauses 168 to 190, wherein the compoundthat inhibits FAK, SRC and JAK2 is administered after the MEK inhibitor.

195. The compound of any one of clauses 168 to 194, wherein the patienthas not received a prior treatment.

196. The compound of any one of clauses 168 to 194, wherein the patienthas received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies.

197. The compound of any one of clauses 168 to 194, or 196, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

198. Use of a compound that inhibits FAK, SRC and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating cancer in a patient incombination with a therapeutically effective amount of a MEK inhibitor,provided that the MEK inhibitor is not trametinib.

199. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating cancer in a patient incombination with a therapeutically effective amount of a MEK inhibitor,provided that the MEK inhibitor is not trametinib, wherein at least onegenetically altered oncogenic gene has been previously identified in thepatient.

200. Use of compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating a cancer in a patient incombination with a therapeutically effective amount of a MEK inhibitor,provided that the MEK inhibitor is not trametinib, wherein the cancer ismediated by at least one genetically altered oncogenic gene.

201. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for use in a method of treating acancer in a patient in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, wherein the method comprises;

-   -   i. identifying at least one genetically altered oncogenic gene        in the patient, and    -   ii. administering to the patient the medicament in combination        with a MEK inhibitor, provided that the MEK inhibitor is not        trametinib.

202. The use of any one of clauses 169 to 171, wherein the at least onegenetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered HRAS, a geneticallyaltered BRAF, a genetically altered MEK, and/or a genetically alteredPI3K.

203. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating non-small cell lungcancer in a patient in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib.

204. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating non-small cell lungcancer in a patient in combination with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, wherein at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K has been previouslyidentified in the patient.

205. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating non-small cell lungcancer mediated by at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS,genetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K in a patient in combinationwith a therapeutically effective amount of a MEK inhibitor, providedthat the MEK inhibitor is not trametinib.

206. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for use in a method of treatingnon-small cell lung cancer in a patient in combination with atherapeutically effective amount of a MEK inhibitor, provided that theMEK inhibitor is not trametinib, the method comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient the medicament in combination        with a MEK inhibitor, provided that the MEK inhibitor is not        trametinib.

207. The use of any one of clauses 204 to 206, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D,G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from the groupconsisting of G12D, G13D, and Q61H.

208. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating colorectal cancer orpancreatic cancer in a patient in combination with a therapeuticallyeffective amount of a MEK inhibitor, provided that the MEK inhibitor isnot trametinib.

209. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating colorectal cancer orpancreatic cancer in a patient in combination with a therapeuticallyeffective amount of a MEK inhibitor, provided that the MEK inhibitor isnot trametinib, wherein at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K has been previouslyidentified in the patient.

210. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for treating colorectal cancer orpancreatic cancer mediated by at least one genetically altered oncogenicgene selected from a genetically altered KRAS, a genetically alteredNRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K in a patient incombination with a therapeutically effective amount of a MEK inhibitor,provided that the MEK inhibitor is not trametinib.

211. Use of a compound that inhibits FAK, SRC, and JAK2, or apharmaceutically acceptable salt thereof, in the preparation of amedicament comprising a therapeutically effective amount of the compoundthat inhibits FAK, SRC, and JAK2, for use in a method of treatingcolorectal cancer or pancreatic cancer in a patient in combination witha therapeutically effective amount of a MEK inhibitor, provided that theMEK inhibitor is not trametinib, the method comprising;

-   -   i. identifying at least one genetically altered oncogenic gene        selected from a genetically altered KRAS, a genetically altered        NRAS, a genetically altered HRAS, a genetically altered BRAF, a        genetically altered MEK, or a genetically altered PI3K in the        patient, and    -   ii. administering to the patient the medicament in combination        with a MEK inhibitor, provided that the MEK inhibitor is not        trametinib.

212. The use of any one of clauses 208 to 210, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K,G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R,A146V, A146P, K147N, and R97I; or selected from the group consisting ofG12D, G12V, G12R, Q61H, G12C, and G12S.

213. The use of any one of clauses 198 to 212, wherein the compound thatinhibits FAK, SRC, and JAK2 is administered in an amount of from about40 mg to about 200 mg.

214. The use of any one of clauses 198 to 213, wherein the compound thatinhibits FAK, SRC, and JAK2 is administered in an amount of about 40 mg,or about 80 mg, or about 120 mg, or about 160 mg.

215. The use of any one of clauses 198 to 214, wherein the compound thatinhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, C(O)NH₂,C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7 memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, CO₂C₁C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

216. The use of any one of clauses 198 to 215, wherein the compound thatinhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

217. The use of any one of clauses 198 to 216, wherein the compound thatinhibits FAK, SRC and JAK2 is administered in an amount of about 40 mg,about 80 mg, about 120 mg, or about 160 mg.

218. The use of any one of clauses 198 to 217, wherein the MEK inhibitoris pimasertib, selumetinib, cobimetinib, PD-0325901, refametinib,TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973, AZD8330,AZD6244, or CI-1040.

219. The use of any one of clauses 198 to 218, wherein the compound thatinhibits FAK, SRC and JAK2 is administered on a schedule of at least onedose of about 40 mg QD. about 80 mg QD, about 120 mg QD, or about 160 mgQD, followed by at least one dose of about 40 mg BID, about 80 mg BID,about 120 mg BID, or about 160 mg BID.

220. The use of any one of clauses 198 to 219, wherein the MEK inhibitoris selumetinib.

221. The use of any one of clauses 198 to 220, wherein the compound thatinhibits FAK, SRC and JAK2 is administered at the same time as the MEKinhibitor.

222. The use of any one of clauses 198 to 220, wherein the compound thatinhibits FAK, SRC and JAK2 is administered prior to the MEK inhibitor.

223. The use of any one of clauses 198 to 220, wherein the compound thatinhibits FAK, SRC and JAK2 is administered after the MEK inhibitor.

224. The use of any one of clauses 198 to 223, wherein the patient hasnot received a prior treatment.

225. The use of any one of clauses 198 to 223, wherein the patient hasreceived at least one prior treatment of one or more chemotherapeuticagents or immunotherapies.

226. The use of any one of clauses 198 to 223 or 225, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

227. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination.

228. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect on a cancer in a patient, wherein at least onegenetically altered oncogenic gene has been previously identified in thepatient.

229. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect on a cancer mediated by at least one geneticallyaltered oncogenic gene.

230. The medicament of clause 228 or 229, wherein the at least onegenetically altered oncogenic gene is a genetically altered KRAS, agenetically altered NRAS, a genetically altered BRAF, a geneticallyaltered MEK, and/or a genetically altered PI3K.

231. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect for treating non-small cell lung cancer.

232. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect for treating non-small cell lung cancer in a patient,wherein at least one genetically altered oncogenic gene selected from agenetically altered KRAS, a genetically altered NRAS, a geneticallyaltered BRAF, a genetically altered MEK, or a genetically altered PI3Khas been previously identified in the patient.

233. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect for treating non-small cell lung cancer mediated byat least one genetically altered oncogenic gene selected from agenetically altered KRAS, a genetically altered NRAS, a geneticallyaltered BRAF, a genetically altered MEK, or a genetically altered PI3Kin a patient.

234. The medicament of clause 232 or 233, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D,G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R, or selected from the groupconsisting of G12D, G13D, and Q61H.

235. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect for treating colorectal cancer or pancreatic cancerin a patient.

236. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect for treating colorectal cancer or pancreatic cancerin a patient, wherein at least one genetically altered oncogenic geneselected from a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K has been previouslyidentified in the patient.

237. A medicament comprising a therapeutically effective amount of acompound that inhibits FAK, SRC, and JAK2, or a pharmaceuticallyacceptable salt thereof, combined with a therapeutically effectiveamount of a MEK inhibitor, provided that the MEK inhibitor is nottrametinib, in fixed or free combination, wherein the medicamentprovides an effect for treating colorectal cancer or pancreatic cancermediated by at least one genetically altered oncogenic gene selectedfrom a genetically altered KRAS, a genetically altered NRAS, agenetically altered HRAS, a genetically altered BRAF, a geneticallyaltered MEK, or a genetically altered PI3K in a patient.

238. The medicament of clause 236 or 237, wherein the geneticallyaltered KRAS comprises at least one mutation selected from the groupconsisting of G12D, G12V, G13D, A146T, G12C, G12A, G12S, K117N, Q61K,G12R, M72V, S17G, K5R, D69G, G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R,A146V, A146P, K147N, and R97I; or selected from the group consisting ofG12D, G12V, G12R, Q61H, G12C, and G12S.

239. The medicament of any one of clauses 227 to 238, wherein thecompound that inhibits FAK, SRC, and JAK2 is provided in the medicamentin an amount of from about 40 mg to about 200 mg.

240. The medicament of any one of clauses 227 to 239, wherein thecompound that inhibits FAK, SRC, and JAK2 is provided in the medicamentin an amount of about 40 mg, or about 80 mg, or about 120 mg, or about160 mg.

241. The medicament of any one of clauses 227 to 240, wherein thecompound that inhibits FAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, C(O)NH₂,C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7 memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, CO₂C₁C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

242. The medicament of any one of clauses 227 to 241, wherein thecompound that inhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

243. The medicament of any one of clauses 227 to 242, wherein thecompound that inhibits FAK, SRC and JAK2 is provided in the medicamentin an amount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg.

244. The medicament of any one of clauses 227 to 243, wherein the MEKinhibitor is pimasertib, selumetinib, cobimetinib, PD-0325901,refametinib, TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973,AZD8330, AZD6244, or CI-1040.

245. The medicament of any one of clauses 227 to 244, wherein thecompound that inhibits FAK, SRC and JAK2 is provided in the medicamenton a schedule of at least one dose of about 40 mg QD, about 80 mg QD,about 120 mg QD, or about 160 mg QD, followed by at least one dose ofabout 40 mg BID, about 80 mg BID, about 120 mg BID, or about 160 mg BID.

246. The medicament of any one of clauses 227 to 245, wherein the MEKinhibitor is selumetinib.

247. The medicament of any one of clauses 227 to 246, wherein thecompound that inhibits FAK, SRC and JAK2 is provided at the same time asthe MEK inhibitor.

248. The medicament of any one of clauses 227 to 246, in freecombination, wherein the compound that inhibits FAK, SRC and JAK2 isprovided prior to the MEK inhibitor.

249. The medicament of any one of clauses 227 to 246, in freecombination, wherein the compound that inhibits FAK, SRC and JAK2 isprovided after the MEK inhibitor.

250. The medicament of any one of clauses 227 to 249, wherein thepatient has not received a prior treatment.

251. The medicament of any one of clauses 227 to 249, wherein thepatient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies.

252. The medicament of any one of clauses 227 to 249, or 251, whereinthe patient has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies, and has developed anacquired resistance to the treatment, and/or developed bypass resistanceto the treatment.

253. A composition of a compound that inhibits FAK, SRC and JAK2 andtrametinib, where the two components come into contact with each otherat a locus.

254. The composition of clause 253, wherein the compound that inhibitsFAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, C(O)NH₂,C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7 memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, CO₂C₁C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

255. The composition of clause 253 or 254, wherein the compound thatinhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

256. The composition of any one of clauses 253 to 255, wherein the locusis a cancer or a cancer cell.

257. The composition of any one of clauses 253 to 256, wherein the locusis a cancer selected from non-small cell lung cancer, colorectal canceror pancreatic cancer and pancreatic cancer.

258. The composition of clause 257, wherein the cancer is non-small celllung cancer.

259. The composition of clause 257, wherein the cancer is colorectalcancer or pancreatic cancer.

260. The composition of any one of clauses 253 to 259, wherein the locuscomprises at least one genetically altered oncogenic gene selected froma genetically altered KRAS, a genetically altered NRAS, a geneticallyaltered HRAS, a genetically altered BRAF, a genetically altered MEK, ora genetically altered PI3K.

261. The composition of any one of clauses 253 to 260, wherein the locuscomprises a genetically altered KRAS having at least one mutationselected from the group consisting of G12C, G12V, G12D, G12A, G13C,G12S, D12R, D12F, G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; orselected from the group consisting of G12A, G12C, G12D, G12S, G12V,G13D, Q61H, and Q61K, or selected from the group consisting of G12D,G13D, and Q61H; or selected from the group consisting of G12D, G12V,G13D, A146T, G12C, G12A, G12S, K117N, Q61K, G12R, M72V, S17G, K5R, D69G,G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R, A146V, A146P, K147N, andR97I; or selected from the group consisting of G12D, G12V, G12R, Q61H,G12C, and G12S.

262. The composition of any one of clauses 253 to 261, wherein thecompound that inhibits FAK, SRC, and JAK2 is provided in the compositionin an amount of from about 40 mg to about 200 mg.

263. The composition of any one of clauses 253 to 262, wherein the MEKinhibitor is pimasertib, selumetinib, cobimetinib, PD-0325901,refametinib, TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973,AZD8330, AZD6244, or CI-1040.

264. The composition of any one of clauses 253 to 263, wherein thecompound that inhibits FAK, SRC and JAK2 is provided in the compositionin an amount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg.

265. The composition of any one of clauses 253 to 264, wherein the MEKinhibitor is selumetinib.

266. A composition of a compound that inhibits FAK, SRC and JAK2 andtrametinib, where the two components come into contact with each otheronly in the human body.

267. The composition of clause 266, wherein the compound that inhibitsFAK, SRC and JAK2 is of the formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; wherein eachhydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, C(O)NH₂,C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7 memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, CO₂C₁C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, N(C₁-C₆ alkyl)S(O)₂NH₂,NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), NHS(O)N(C₁-C₆ alkyl)₂,NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, SC₁-C₆ alkyl, S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, P(C₁-C₆ alkyl)₂, —P(O)(C₁-C₆alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or —CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

268. The composition of clause 266 or 267, wherein the compound thatinhibits FAK, SRC and JAK2 is a compound of the formula

or a pharmaceutically acceptable salt thereof.

269. The composition of any one of clauses 266 to 268, wherein the humanbody comprises at least one genetically altered oncogenic gene selectedfrom a genetically altered KRAS, a genetically altered NRAS, agenetically altered BRAF, a genetically altered MEK, or a geneticallyaltered PI3K.

270. The composition of any one of clauses 266 to 269, wherein the humanbody comprises a genetically altered KRAS having at least one mutationselected from the group consisting of G12C, G12V, G12D, G12A, G13C,G12S, D12R, D12F, G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; orselected from the group consisting of G12A, G12C, G12D, G12S, G12V,G13D, Q61H, and Q61K, or selected from the group consisting of G12D,G13D, and Q61H; or selected from the group consisting of G12D, G12V,G13D, A146T, G12C, G12A, G12S, K117N, Q61K, G12R, M72V, S17G, K5R, D69G,G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R, A146V, A146P, K147N, andR97I; or selected from the group consisting of G12D, G12V, G12R, Q61H,G12C, and G12S.

271. The composition of any one of clauses 266 to 270, wherein thecompound that inhibits FAK, SRC, and JAK2 is provided in the compositionin an amount of from about 40 mg to about 200 mg.

272. The composition of any one of clauses 266 to 271, wherein the MEKinhibitor is pimasertib, selumetinib, cobimetinib, PD-0325901,refametinib, TAK733, MEK162, RO5126766, WX-554, RO4987655, GDC-0973,AZD8330, AZD6244, or CI-1040.

273. The composition of any one of clauses 266 to 272, wherein thecompound that inhibits FAK, SRC and JAK2 is provided in the compositionin an amount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg.

274. The composition of any one of clauses 266 to 273, wherein the MEKinhibitor is selumetinib.

275. The composition of any one of clauses 266 to 274, wherein the humanbody has not received a prior treatment.

276. The composition of any one of clauses 266 to 274, wherein the humanbody has received at least one prior treatment of one or morechemotherapeutic agents or immunotherapies.

277. The composition of any one of clauses 266 to 274, or 276, whereinthe host animal is a human patient in need of such treatment who hasreceived at least one prior treatment of one or more chemotherapeuticagents or immunotherapies, and developed an acquired resistance to thetreatment or developed bypass resistance to the treatment.

278. The method, use, compound, composition, or medicament of any one ofthe preceding claims, wherein the MEK inhibitor is trametinib,selumetinib, LY3214996, RO5126766, TNO155 (SHP099), or mirdametinib, ora pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a shows the level of caspase-3/7 activated by Compound 1 (1 μM),trametinib (50 nM) and Compound 1 (1 μM)+trametinib (50 nM) at 24 hr and48 hr timepoints in NCI-H358 cells with KRAS G12C mutation.

FIG. 1b shows the level of caspase-3/7 activated by Compound 1 (1 μM),trametinib (50 nM) and Compound 1 (1 μM)+trametinib (50 nM) at 24 hr and48 hr timepoints in Calu-6 cells with KRAS Q61K mutation.

FIG. 1c shows the level of caspase-3/7 activated by Compound 1 (1 μM),trametinib (50 nM) and Compound 1 (1 μM)+trametinib (50 nM) at 24 hr and48 hr timepoints in NCI-H2122 cells with KRAS G12C mutation.

FIG. 1d shows the level of caspase-3/7 activated by Compound 1 (1 μM),trametinib (50 nM) and Compound 1 (1 μM)+trametinib (50 nM) at 24 hr and48 hr timepoints in NCI-H441 cells with KRAS G12V mutation.

FIG. 2a is a chart showing the antitumor effect of Compound 1 incombination with trametinib in Calu-6 cell-derived xenograft tumorsharboring the KRAS^(Q61K) mutation in athymic nude mice. (●) Control;(▾) Compound 1 (15 mg/kg BID); (Δ) Trametinib (0.2 mg/kg QD); (▴)Compound 1 (15 mg/kg BID) plus Trametinib (0.2 mg/kg QD); (□) Trametinib(0.6 mg/kg QD); (▪) Compound 1 (15 mg/kg BID) plus Trametinib (0.6 mg/kgQD).

FIG. 2b is a chart showing the body weight of mice bearing Calu-6cell-derived xenograft tumors harboring the KRAS^(Q61K) mutation whentreated with: (●) Control; (▾) Compound 1 (15 mg/kg BID); (Δ) Trametinib(0.2 mg/kg QD); (▴) Compound 1 (15 mg/kg BID) plus Trametinib (0.2 mg/kgQD); (□) Trametinib (0.6 mg/kg QD); (▪) Compound 1 (15 mg/kg BID) plusTrametinib (0.6 mg/kg QD). The body weight data was obtained from thesame cohort of mice as in FIG. 2 a.

FIG. 3 shows pharmacodynamic modulation of phosphor-EGFR, phosphor-SRC,phosphor-FAK, and phosphoERK following treatment with the MEK1/2inhibitor trametinib (0.6 mg/kg QD), Compound 1 (15 mg/kg BID), andtrametinib (0.6 mg/kg QD) in the presence of Compound 1 (15 mg/kg BID)in Calu-6 cell-derived xenograft tumors harboring the KRAS^(Q61K)mutation. mpk: mg/kg.

FIG. 4a is a chart showing the antitumor effect of Compound 1 incombination with trametinib in HCT-116 cell-derived xenograft tumorsharboring the KRAS^(G13D) mutation in SCID/Beige mice. (●) Control; (▾)Compound 1 (15 mg/kg BID); (▴) Trametinib (0.4 mg/kg QD); (▪) Compound 1(15 mg/kg BID) plus Trametinib (0.4 mg/kg QD).

FIG. 4b shows body weights of mice bearing HCT-116 cell-derivedxenograft tumors harboring the KRAS^(G13D) mutation when treated with:(●) Control; (▾) Compound 1 (15 mg/kg BID); (▴) Trametinib (0.4 mg/kgQD); (▪) Compound 1 (15 mg/kg BID) plus Trametinib (0.4 mg/kg QD). Thebody weight data was obtained from the same cohort of mice as in FIG. 4a.

FIG. 5a is a chart showing the antitumor effect of Compound 1 incombination with trametinib in mLU6045 MuPrime mouse lung cancer modelwith KRAS^(G12D/+); p53^(−/−) mutations in C57BL/6 mice. (●) Control;(▾) Compound 1 (15 mg/kg BID); ( ) Trametinib (1 mg/kg QD); (▪) Compound1 (15 mg/kg BID) plus Trametinib (1 mg/kg QD).

FIG. 5b is a chart showing the body weight of mice bearing mLU6045MuPrime mouse tumors with the KRAS^(G12D/+); p53^(−/−) mutations whentreated with: (●) Control; (▾) Compound 1 (15 mg/kg BID); ( ) Trametinib(1 mg/kg QD); (▪) Compound 1 (15 mg/kg BID) plus Trametinib (1 mg/kgQD). The body weight data was obtained from the same cohort of mice asin FIG. 5 a.

DETAILED DESCRIPTION

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties. If a definition set forthin this section is contrary to or otherwise inconsistent with adefinition set forth in a patent, application, or other publication thatis herein incorporated by reference, the definition set forth in thissection prevails over the definition incorporated herein by reference.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. It is further noted that the claims may be drafted to excludeany optional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

Chemical nomenclature for compounds described herein has generally beenderived using the commercially-available ACD/Name 2014 (ACD/Labs) orChemBioDraw Ultra 13.0 (Perkin Elmer).

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present invention and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterized, and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentinvention and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

The methods described herein are used to treat a “host animal” withcancer in need of such treatment. In one embodiment, the methodsdescribed herein can be used for both human clinical medicine andveterinary applications. Thus, a “host animal” can be administered thecombinations described herein, and the host animal can be human (e.g., ahuman patient, a.k.a. a patient) or, in the case of veterinaryapplications, can be a laboratory, agricultural, or domestic animal. Inone aspect, the host animal can be a human, or a laboratory animal suchas a rodent (e.g., mice, rats, etc.), and the like.

As used herein, the term “cancer” includes, but is not limited to, ALCL,lung cancer, such as non-small cell lung cancer (NSCLC), includingadenocarcinoma, lung squamous cell carcinoma, large cell carcinoma, andlarge cell neuroendocrine tumors, small cell lung cancer (SCLC),neuroblastoma, inflammatory myofibroblastic tumor, adult renal cellcarcinoma, pediatric renal cell carcinoma, breast cancer, such as triplenegative breast cancer, triple positive breast cancer, colonicadenocarcinoma, glioblastoma, glioblastoma multiforme, thyroid cancer,such as anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer,gastric cancer, such as gastric adenocarcinoma, colorectal cancer (CRC),inflammatory myofibroblastic tumor, angiosarcoma, epithelioidhemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillarycancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower gradeglioma, secretory breast carcinoma, mammary analogue carcinoma, acutemyeloid leukemia, congenital mesoblastic nephroma, congenitalfibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma,skin cancer, such as skin cutaneous melanoma, head and neck squamouscell carcinoma (HNSCC), pediatric glioma CML, prostate cancer, ovarianserous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistantprostate cancer, Hodgkin lymphoma, and serous and clear cell endometrialcancer. It will be appreciated that the term “cancer” includes bothprimary cancers or primary tumors and metastatic cancers or metastatictumors. For example, metastatic NSCLC, metastatic CRC, metastaticpancreatic cancer, metastatic colorectal carcinoma, metastatic HNSCC,and the like. It will be appreciated that the term “cancer” includescancers that involve the upregulation of certain genes or geneticmutations in certain genes that can lead to disease progression, suchup-regulation of epidermal growth factor receptor.

In particular, in some embodiments of the various aspects describedherein, the cancer is mediated by at least one genetically alteredoncogenic gene selected from a genetically altered KRAS, a geneticallyaltered NRAS, a genetically altered HRAS, a genetically altered BRAF, agenetically altered MEK, or a genetically altered PI3K, or suchgenetically altered oncogenic gene has been identified in the patient.In some embodiments of the various aspects described herein, the canceris non-small cell lung cancer mediated by a genetically altered KRAScomprising at least one mutation selected from the group consisting ofG12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R, G13E,Q61H, Q61E, Q61L, and Q61R. In some embodiments of the various aspectsdescribed herein, the cancer is non-small cell lung cancer mediated by agenetically altered KRAS comprising at least one mutation selected fromthe group consisting of G12D, G13D, and Q61H; In some embodiments of thevarious aspects described herein, the cancer is non-small cell lungcancer mediated by a genetically altered KRAS comprising at least onemutation that is not G12A, G12C, G12S, G12V, or Q61K.

In some embodiments of the various aspects described herein, the canceris colorectal cancer mediated by a genetically altered KRAS comprisingat least one mutation selected from the group consisting of G12D, G12V,G13D, A146T, G12C, G12A, G12S, K117N, Q61K, G12R, M72V, S17G, K5R, D69G,G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R, A146V, A146P, K147N, andR97I.

In some embodiments of the various aspects described herein, the canceris pancreatic cancer mediated by a genetically altered KRAS comprisingat least one mutation selected from the group consisting of G12D, G12V,G12R, Q61H, G12C, and G12S.

As used herein, the term “KRAS” refers to the KRAS gene, thecorresponding mRNA resulting from transcription of the KRAS gene, or theprotein encoded by the KRAS gene, called K-Ras, that is involved in theRAS/MAPK signaling pathway. The terms KRAS gene, K-Ras, and RAS/MAPKsignaling pathway will be known and understood by one of skill in theart. It will be appreciated that KRAS mutations occur in approximatelyone in seven of all human metastatic cancers, and that those mutationscan occur in a variety of locations in the KRAS gene coding sequence.KRAS mutations primarily occur in KRAS codons 12 and 13, and also occurin codons 18, 61, 117, and 146 at low frequencies and have distincteffects on tumor cell signaling based on the codon and missensemutation. Examples of KRAS mutations include, but are not limited toKRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRASA18D, KRAS Q61H, KRAS K117N, and the like.

Chemical Definitions

As used herein “Mek inhibitor” or “MEK inhibitor” includes, but is notlimited to, any compound or agent known in the art to inhibit theMAPK/ERK kinase-1 and -2 gene or inhibit the protein encoded by theMAPK/ERK kinase-1 and -2 gene (MEK1 and MEK2; MAP2K1 and MAP2K2).Exemplary Mek inhibitors for use in connection with the methods andcompositions described herein include, but are not limited to,trametinib, pimasertib (AST03026); selumetinib (AZD6244); cobimetinib;mirdametinib (PD-0325901); refametinib (RDEA119); TAK733; MEK162;RO5126766; WX-554; RO4987655; GDC-0973; AZD8330; AZD6244; and CI-1040(PD-184352); GDC-0623; HL-085.

As used herein, the term “trametinib” refers to a compound having theformula

or a pharmaceutically acceptable salt thereof, which is also known asGSK1120212 orN-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide.Trametinib is an orally bioavailable inhibitor of mitogen-activatedprotein kinase kinase (MEK MAPK/ERK kinase) with potentialantineoplastic activity. Trametinib specifically binds to and inhibitsMEK 1 and 2, resulting in an inhibition of growth factor-mediated cellsignaling and cellular proliferation in various cancers.

As used herein, the term “alkyl” includes a chain of carbon atoms, whichis optionally branched and contains from 1 to 20 carbon atoms. It is tobe further understood that in certain embodiments, alkyl may beadvantageously of limited length, including C₁-C₁₂, C₁-C₉, C₁-C₈, C₁-C₇,C₁-C₆, and C₁-C₄, Illustratively, such particularly limited length alkylgroups, including C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄, and the like may bereferred to as “lower alkyl.” Illustrative alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl,heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted.Typical substituent groups include cycloalkyl, aryl, heteroaryl,heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio,arylthio, cyano, halo, carbonyl, oxo, (═O), thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy,O-carboxy, nitro, and amino, or as described in the various embodimentsprovided herein. It will be understood that “alkyl” may be combined withother groups, such as those provided above, to form a functionalizedalkyl. By way of example, the combination of an “alkyl” group, asdescribed herein, with a “carboxy” group may be referred to as a“carboxyalkyl” group. Other non-limiting examples include hydroxyalkyl,aminoalkyl, and the like.

As used herein, the term “alkenyl” includes a chain of carbon atoms,which is optionally branched, and contains from 2 to 20 carbon atoms,and also includes at least one carbon-carbon double bond (i.e. C═C). Itwill be understood that in certain embodiments, alkenyl may beadvantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇,C₂-C₆, and C₂-C₄. Illustratively, such particularly limited lengthalkenyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referredto as lower alkenyl. Alkenyl may be unsubstituted, or substituted asdescribed for alkyl or as described in the various embodiments providedherein. Illustrative alkenyl groups include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

As used herein, the term “alkynyl” includes a chain of carbon atoms,which is optionally branched, and contains from 2 to 20 carbon atoms,and also includes at least one carbon-carbon triple bond (i.e. CC). Itwill be understood that in certain embodiments, alkynyl may each beadvantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇,C₂-C₆, and C₂-C₄. Illustratively, such particularly limited lengthalkynyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referredto as lower alkynyl. Alkenyl may be unsubstituted, or substituted asdescribed for alkyl or as described in the various embodiments providedherein. Illustrative alkenyl groups include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

As used herein, the term “aryl” refers to an all-carbon monocyclic orfused-ring polycyclic groups of 6 to 12 carbon atoms having a completelyconjugated pi-electron system. It will be understood that in certainembodiments, aryl may be advantageously of limited size such as C₆-C₁₀aryl. Illustrative aryl groups include, but are not limited to, phenyl,naphthalenyl and anthracenyl. The aryl group may be unsubstituted, orsubstituted as described for alkyl or as described in the variousembodiments provided herein.

As used herein, the term “cycloalkyl” refers to a 3 to 15 memberall-carbon monocyclic ring, including an all-carbon 5-member/6-member or6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares anadjacent pair of carbon atoms with each other ring in the system) group,where one or more of the rings may contain one or more double bonds butthe cycloalkyl does not contain a completely conjugated pi-electronsystem. It will be understood that in certain embodiments, cycloalkylmay be advantageously of limited size such as C₃-C₁₃, C₃-C₉, C₃-C₆ andC₄-C₆. Cycloalkyl may be unsubstituted, or substituted as described foralkyl or as described in the various embodiments provided herein.Illustrative cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl,cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl,norbornenyl, 9H-fluoren-9-yl, and the like. Illustrative examples ofcycloalkyl groups shown in graphical representations include thefollowing entities, in the form of properly bonded moieties:

As used herein, the term “heterocycloalkyl” refers to a monocyclic orfused ring group having in the ring(s) from 3 to 12 ring atoms, in whichat least one ring atom is a heteroatom, such as nitrogen, oxygen orsulfur, the remaining ring atoms being carbon atoms. Heterocycloalkylmay optionally contain 1, 2, 3 or 4 heteroatoms. Heterocycloalkyl mayalso have one of more double bonds, including double bonds to nitrogen(e.g. C═N or N═N) but does not contain a completely conjugatedpi-electron system. It will be understood that in certain embodiments,heterocycloalkyl may be advantageously of limited size such as 3- to7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and thelike. Heterocycloalkyl may be unsubstituted, or substituted as describedfor alkyl or as described in the various embodiments provided herein.Illustrative heterocycloalkyl groups include, but are not limited to,oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl,5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and thelike. Illustrative examples of heterocycloalkyl groups shown ingraphical representations include the following entities, in the form ofproperly bonded moieties:

As used herein, the term “heteroaryl” refers to a monocyclic or fusedring group of 5 to 12 ring atoms containing one, two, three or four ringheteroatoms selected from nitrogen, oxygen and sulfur, the remainingring atoms being carbon atoms, and also having a completely conjugatedpi-electron system. It will be understood that in certain embodiments,heteroaryl may be advantageously of limited size such as 3- to7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like.Heteroaryl may be unsubstituted, or substituted as described for alkylor as described in the various embodiments provided herein. Illustrativeheteroaryl groups include, but are not limited to, pyrrolyl, furanyl,thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl,pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl,pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl andcarbazoloyl, and the like. Illustrative examples of heteroaryl groupsshown in graphical representations, include the following entities, inthe form of properly bonded moieties:

As used herein, “hydroxy” or “hydroxyl” refers to an —OH group.

As used herein, “alkoxy” refers to both an —O-(alkyl) or an—O-(unsubstituted cycloalkyl) group. Representative examples include,but are not limited to, methoxy, ethoxy, propoxy, butoxy,cyclopropyloxy, cyclobutyloxy, cycl op entyl oxy, cyclohexyloxy, and thelike.

As used herein, “aryloxy” refers to an —O-aryl or an —O-heteroarylgroup. Representative examples include, but are not limited to, phenoxy,pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, andthe like, and the like.

As used herein, “mercapto” refers to an —SH group.

As used herein, “alkylthio” refers to an —S-(alkyl) or an—S-(unsubstituted cycloalkyl) group. Representative examples include,but are not limited to, methylthio, ethylthio, propylthio, butylthio,cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, andthe like.

As used herein, “arylthio” refers to an —S-aryl or an —S-heteroarylgroup. Representative examples include, but are not limited to,phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio,and the like.

As used herein, “halo” or “halogen” refers to fluorine, chlorine,bromine or iodine.

As used herein, “cyano” refers to a —CN group.

The term “oxo” represents a carbonyl oxygen. For example, a cyclopentylsubstituted with oxo is cyclopentanone.

As used herein, “bond” refers to a covalent bond.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. Where the term “substituted” isused to describe a structural system, the substitution is meant to occurat any valency-allowed position on the system. In some embodiments,“substituted” means that the specified group or moiety bears one, two,or three substituents. In other embodiments, “substituted” means thatthe specified group or moiety bears one or two substituents. In stillother embodiments, “substituted” means the specified group or moietybears one substituent.

As used herein, “optional” or “optionally” means that the subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “wherein each hydrogenatom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclicheteroaryl is independently optionally substituted by C₁-C₆ alkyl” meansthat an alkyl may be but need not be present on any of the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, or mono- or bicyclic heteroaryl byreplacement of a hydrogen atom for each alkyl group, and the descriptionincludes situations where the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, ormono- or bicyclic heteroaryl is substituted with an alkyl group andsituations where the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or mono- orbicyclic heteroaryl is not substituted with the alkyl group.

As used herein, “independently” means that the subsequently describedevent or circumstance is to be read on its own relative to other similarevents or circumstances. For example, in a circumstance where severalequivalent hydrogen groups are optionally substituted by another groupdescribed in the circumstance, the use of “independently optionally”means that each instance of a hydrogen atom on the group may besubstituted by another group, where the groups replacing each of thehydrogen atoms may be the same or different. Or for example, wheremultiple groups exist all of which can be selected from a set ofpossibilities, the use of “independently” means that each of the groupscan be selected from the set of possibilities separate from any othergroup, and the groups selected in the circumstance may be the same ordifferent.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which counter ions which may be used in pharmaceuticals.See, generally, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm.Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts arethose that are pharmacologically effective and suitable for contact withthe tissues of subjects without undue toxicity, irritation, or allergicresponse. A compound described herein may possess a sufficiently acidicgroup, a sufficiently basic group, both types of functional groups, ormore than one of each type, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Such salts include:

(1) acid addition salts, which can be obtained by reaction of the freebase of the parent compound with inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, andperchloric acid and the like, or with organic acids such as acetic acid,oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaricacid, citric acid, succinic acid or malonic acid and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,trimethamine, N-methylglucamine, and the like.

Pharmaceutically acceptable salts are well known to those skilled in theart, and any such pharmaceutically acceptable salt may be contemplatedin connection with the embodiments described herein. Examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates,propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, and mandelates. Lists of other suitable pharmaceuticallyacceptable salts are found in Remington's Pharmaceutical Sciences, 17thEdition, Mack Publishing Company, Easton, Pa., 1985.

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. For example,a formula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or a mixturethereof. Additionally, any formula given herein is intended to referalso to a hydrate, solvate, or polymorph of such a compound, or amixture thereof. For example, it will be appreciated that compoundsdepicted by a structural formula containing the symbol “

” include both stereoisomers for the carbon atom which the symbol “

” is attached, specifically both the bonds “

” are “

” encompassed by the meaning of “

”.

For example, in some exemplary embodiments, certain compounds providedherein can be described by the formula

which formula will be understood to encompass compounds having allstereochemical configurations at the relevant carbon atoms, including

Embodiments

In some embodiments, the methods described herein relate to thetreatment of cancer comprising administering to a patient in need oftreatment a therapeutically effective amount of one or more compoundsthat inhibit FAK, SRC and/or JAK2 in combination with trametinib. Insome embodiments, the methods described herein relate to the treatmentof cancer comprising administering to a patient in need of treatment atherapeutically effective amount of a compound that inhibits FAK, SRCand JAK2 in combination with trametinib. It will be appreciated that aninhibitor is any substance that reduces or suppresses the activity ofanother substance, such as a cell surface receptor (i.e. a receptortyrosine kinase), or a kinase (i.e. a non-receptor tyrosine kinase), orthe transcription and/or translation of a gene. It will be appreciatedthat “a compound that inhibits FAK, SRC and JAK2” is a compound that hasaffinity for all three of the biological targets FAK, SRC and JAK2.

It has been discovered that certain compounds described herein have beensurprisingly shown to be inhibitors of FAK, SRC and JAK2, and can beused in combination with trametinib to treat cancer in a patient in needof such treatment. In some embodiments, the combination of one or morecompounds that inhibit FAK, SRC and/or JAK2 with trametinib can providea synergistic response in a patient in need of treatment for cancer. Insome embodiments, the combination of a compound that inhibits FAK, SRCand JAK2 with trametinib can provide a synergistic response in a patientin need of treatment for cancer. In some embodiments, methods fortreating cancer comprising administering a combination of atherapeutically effective amount of a compound that inhibits FAK, SRCand JAK2 and a therapeutically effective amount of trametinib. In someembodiments, the compound that inhibits FAK, SRC and JAK2 and trametinibare co-formulated. In some embodiments, the compound that inhibits FAK,SRC and JAK2 and trametinib are administered at the same time. In someembodiments, the compound that inhibits FAK, SRC and JAK2 and trametinibare individually formulated, and administered at the same time. In someembodiments, the compound that inhibits FAK, SRC and JAK2 and trametinibare individually formulated, and administered in sequence. In someembodiments, the sequential administration of the compound that inhibitsFAK, SRC and JAK2 and trametinib can be accomplished with the compoundthat inhibits FAK, SRC and JAK2 administered first, and trametinibadministered second. In some embodiments, the sequential administrationof the compound that inhibits FAK, SRC and JAK2 and trametinib can beaccomplished with agent that inhibits KRAS G12C administered first, andthe compound that inhibits FAK, SRC and JAK2 administered second.

In some embodiments, the compound that inhibits FAK, SRC and JAK2 is ofthe formula I

wherein

M is CR⁵ or N;

X¹ and X² are independently —C(R⁷)(R⁸)—, —S—, —S(O)—, —S(O)₂—, —O— or—N(R⁹)—;

each R¹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or —C(O)NR⁷R⁸; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl and C₆-C₁₀ aryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R² and R³ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, —C(O)OR⁷ or—C(O)NR⁷R⁸; wherein each hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl and C₆-C₁₀ aryl is independentlyoptionally substituted by deuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NHC(O)C₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)C₁-C₆ alkyl, —NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)NH₂, —N(C₁-C₆ alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

R⁴ and R⁵ are each independently H, fluoro, chloro, bromo, C₁-C₆ alkyl,—OH, —CN, —OC₁-C₆ alkyl, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂ or —CF₃;

R⁶ is H, C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl, wherein eachhydrogen atom in C₁-C₆ alkyl or 3- to 7-membered heterocycloalkyl isindependently optionally substituted by halogen, —OH, —CN, —OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —CO₂H, —CO₂C₁-C₆ alkyl,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3-to 7-membered heterocycloalkyl;

each R⁷ and R⁸ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl or 5- to 7-membered heteroaryl; whereineach hydrogen atom in C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to7-membered heteroaryl is independently optionally substituted bydeuterium, halogen, —OH, —CN, —OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)C₁-C₆ alkyl,—NHC(O)NH₂, —NHC(O)NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)C(O)NH₂, —N(C₁-C₆alkyl)C(O)NHC₁-C₆ alkyl, —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(O)OC₁-C₆ alkyl, —NHS(O)(C₁-C₆ alkyl), —NHS(O)₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)S(O)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl),—NHS(O)NH₂, NHS(O)₂NH₂, —N(C₁-C₆ alkyl)S(O)NH₂, —N(C₁-C₆ alkyl)S(O)₂NH₂,—NHS(O)NH(C₁-C₆ alkyl), —NHS(O)₂NH(C₁-C₆ alkyl), —NHS(O)N(C₁-C₆ alkyl)₂,—NHS(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)S(O)₂NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂N(C₁-C₆ alkyl)₂, —CO₂H, —C(O)OC₁-C₆ alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —SC₁-C₆ alkyl, —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆ alkyl, —S(O)NH(C₁-C₆ alkyl), —S(O)₂NH(C₁-C₆ alkyl),—S(O)N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —P(C₁-C₆ alkyl)₂,—P(O)(C₁-C₆ alkyl)₂, C₃-C₆ cycloalkyl, or 3- to 7-memberedheterocycloalkyl;

each R⁹ is independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom inC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 7-membered heteroarylis independently optionally substituted by deuterium, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or —OW;

each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is independently N, NH, or C(R¹⁰),wherein each R¹⁰ is independently H, deuterium, halogen, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —OH, —NH₂, —NH(C₁-C₆ alkyl), —NH(phenyl),—NH(heteroaryl), —CN, or CF₃, and

provided that at least one of Z¹, Z², Z³, Z⁴, Z⁵, Z⁶ or Z⁷ is N or NH;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is H or C₁-C₆ alkyl. In some embodiments, R¹ isH or methyl. In some embodiments, one of R¹ is H and the other of R¹ ismethyl. In some embodiments, R² is H. In some embodiments, R² is C₁-C₆alkyl. In some embodiments, one of R² is H and the other of R² ismethyl. In some embodiments, X¹ is —NR⁹—. In some embodiments, R⁹ is H.In some embodiments, X¹ is CHR⁷. In some embodiments, R⁷ is H. In someembodiments, X² is —O—. In some embodiments, R⁶ is H. In someembodiments, R⁴ is F. In some embodiments, M is CR⁵, and R⁵ is H.

Macrocyclic compounds that have been shown herein to be potentsmall-molecule multi-target kinase inhibitors showing activity againstFAK, SRC and JAK2 include, but are not limited to,(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one(also herein referred to as “Compound 1”), represented by the formula

Compound 1 has properties, including anti-tumor properties, which arepharmacologically mediated through inhibition of receptor andnon-receptor tyrosine kinases. Compound 1 is disclosed in InternationalPatent Publication WO2015/112806, which is incorporated herein byreference for the preparation of Compound 1.

In some embodiments of the above aspects, the compound that inhibitsFAK, SRC and JAK2 is of the formula

or a pharmaceutically acceptable salt thereof.

It will be appreciated that the cancer can be any cancer that may bemediated by or associated with KRAS, or the upregulation of KRAS,including but not limited to, ALCL, NSCLC, neuroblastoma, inflammatorymyofibroblastic tumor, adult renal cell carcinoma, pediatric renal cellcarcinoma, breast cancer, triple negative breast, colonicadenocarcinoma, glioblastoma, glioblastoma multiforme, anaplasticthyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer,inflammatory myofibroblastic tumor, angiosarcoma, epithelioidhemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer,spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma,secretory breast carcinoma, mammary analogue carcinoma, acute myeloidleukemia, congenital mesoblastic nephroma, congenital fibrosarcomas,Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and necksquamous cell carcinoma, pediatric glioma CML, prostate cancer, lungsquamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneousmelanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, serousand clear cell endometrial cancer, oral cancer, endometrial cancer,endocrine cancer, skin cancer, gastric cancer, esophageal cancer,laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bonecancer, cervical cancer, uterine cancer, testicular cancer, rectalcancer, kidney cancer, liver cancer, stomach cancer and lung cancer.

In some embodiments of the various aspects described herein, the canceris non-small cell lung cancer mediated by a genetically altered KRAScomprising at least one mutation selected from the group consisting ofG12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R, G13E,Q61H, Q61E, Q61L, and Q61R. In some embodiments of the various aspectsdescribed herein, the cancer is non-small cell lung cancer mediated by agenetically altered KRAS comprising at least one mutation selected fromthe group consisting of G12D, G13D, and Q61H; In some embodiments of thevarious aspects described herein, the cancer is non-small cell lungcancer mediated by a genetically altered KRAS comprising at least onemutation that is not G12A, G12C, G12S, G12V, or Q61K.

In some embodiments of the various aspects described herein, the canceris colorectal cancer mediated by a genetically altered KRAS comprisingat least one mutation selected from the group consisting of G12D, G12V,G13D, A146T, G12C, G12A, G12S, K117N, Q61K, G12R, M72V, S17G, K5R, D69G,G13C, G13R, Q61H, K117E, Q61L, Q61R, K117R, A146V, A146P, K147N, andR97I.

In some embodiments of the various aspects described herein, the canceris pancreatic cancer mediated by a genetically altered KRAS comprisingat least one mutation selected from the group consisting of G12D, G12V,G12R, Q61H, G12C, and G12S.

In some embodiments, the present disclosure provides methods of treatingdisease in a patient that has received no prior treatment. In someembodiments, the present disclosure provides methods of treating diseasein a patient that has received a prior treatment with one or moretherapeutic agents. In some embodiments, the patient has been previouslytreated with one or more chemotherapeutic agents. In still otherembodiments, the patent has been previously treated with one or morechemotherapeutic agents or immunotherapies and developed an acquiredresistance to the treatment. In still other embodiments, the patent hasbeen previously treated with one or more chemotherapeutic agents orimmunotherapies and developed bypass resistance to the treatment. Instill other embodiments, the patent has been previously treated with oneor more chemotherapeutic agents or immunotherapies and developed bypassresistance to the treatment regulated by FAK, SRC or JAK2, and/or FAK.

Other chemotherapeutic agents which the patient may be been treated withprior to treatment with one or more of the compounds or biologicalagents described herein include but are not limited to kinaseinhibitors, adrenocorticoids and corticosteroids, alkylating agents,peptide and peptidomimetic signal transduction inhibitors,antiandrogens, antiestrogens, androgens, aclamycin and aclamycinderivatives, estrogens, antimetabolites, platinum compounds, amanitins,plant alkaloids, mitomycins, discodermolides, microtubule inhibitors,epothilones, inflammatory and proinflammatory agents, purine analogs,pyrimidine analogs, camptothecins, dolastatins, and or immunotherapies.In some embodiments, the patient has been administered a prior treatmentfor NSCLC, such as pembrolizumab, platinum, platinum doublet,pemetrexed, carboplatin, paclitaxel, bevacizumab, atezolizumab,abraxane, and combinations thereof. In some embodiments, the patient hasbeen administered a prior treatment for NSCLC cancer that is thestandard of care using one or more agents selected from the groupconsisting of pembrolizumab, platinum, platinum doublet, pemetrexed,carboplatin, paclitaxel, bevacizumab, atezolizumab, and abraxane.

In some embodiments, the patient has been administered a prior treatmentfor colorectal cancer, such as fluorouracil (5-FU), leucovorin,irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab,panitumumab, ziv-aflibercept, ramucirumab, pemborlizumab, nivolumab,ipilimumab, encorafenib, binimetinib, and combinations thereof. In someembodiments, the patient has been administered a prior treatment forcolorectal cancer that is the standard of care using one or more agentsselected from the group consisting of FOLFOX (i.e.5-FU+leucovorin+irinotecan)+/−bevacizumab, panitumumab or cetuximab,CAPEOX (i.e. oxaliplatin+capecitabine)+/−bevacizumab, FOLFIRI (i.e.5-FU+leucovorin+irinotecan)+/−bevacizumab, cetuximab, panitumumab,ziv-aflibercept or ramucirumab, FOLFOXIRI (i.e. irinotecan, oxaliplatin,leucovorin, 5-FU), irinotecan+cetuximab, panitumumab, or amucirumab,pemborlizumab, nivolumab, nivolumab+ipilimumab, encorafenib, andbinimetinib. In some embodiments, the patient has been administered aprior treatment for pancreatic cancer, such as fluorouracil (5-FU),leucovorin, irinotecan, liposomal irinotecan, oxaliplatin, gemcitabine,abraxane, erlotinib, capecitabine, and combinations thereof.

In some embodiments, the patient has been administered a prior treatmentfor pancreatic cancer that is the standard of care using one or moreagents selected from the group consisting of FOLFIRINOX (i.e.5-FU+leucovorin+irinotecan+oxaliplatin), gemcitabine+abraxane,gemcitabine+erlotinib, gemcitabine, 5-FU+liposomal irinotecan, FOLFIRI(i.e. 5-FU+leucovorin+irinotecan), FOLFOX (i.e. 5-FU, oxaliplatin,leucovorin), and capecitabine+/−oxaliplatin.

In some embodiments, the patient has been administered a prior treatmentfor uterine cancer (a.k.a. endometrial cancer), such as carboplatin,cisplatin, paclitaxel, docetaxel, doxorubicin, liposomal doxorubicin,trastuzumab, topotecan, bevacizumab, temsirolimus tamoxifen,fulvestrant, an aromatase inhibitor, and combinations thereof. In someembodiments, the patient has been administered a prior treatment forpancreatic cancer that is the standard of care using one or more agentsselected from the group consisting ofcarboplatin+paclitaxel+/−trastuzumab, carboplatin orcisplatin+docetaxel, doxorubicin, or paclitaxel, liposomal doxorubicin,topotecan, bevacizumab, temsirolimus tamoxifen, fulvestrant, and anaromatase inhibitor.

Pharmaceutical Compositions

For treatment purposes, pharmaceutical compositions comprising thecompounds described herein may further comprise one or morepharmaceutically-acceptable excipients. A pharmaceutically-acceptableexcipient is a substance that is non-toxic and otherwise biologicallysuitable for administration to a subject. Such excipients facilitateadministration of the compounds described herein and are compatible withthe active ingredient. Examples of pharmaceutically-acceptableexcipients include stabilizers, lubricants, surfactants, diluents,anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, ortaste-modifying agents. In preferred embodiments, pharmaceuticalcompositions according to the invention are sterile compositions.Pharmaceutical compositions may be prepared using compounding techniquesknown or that become available to those skilled in the art.

Sterile compositions are also contemplated by the invention, includingcompositions that are in accord with national and local regulationsgoverning such compositions.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, or dispersions insuitable pharmaceutical solvents or carriers, or as pills, tablets,lozenges, suppositories, sachets, dragees, granules, powders, powdersfor reconstitution, or capsules along with solid carriers according toconventional methods known in the art for preparation of various dosageforms. Pharmaceutical compositions of the invention may be administeredby a suitable route of delivery, such as oral, parenteral, rectal,nasal, topical, or ocular routes, or by inhalation. Preferably, thecompositions are formulated for intravenous or oral administration.

For oral administration, the compounds the invention may be provided ina solid form, such as a tablet or capsule, or as a solution, emulsion,or suspension. To prepare the oral compositions, the compounds of theinvention may be formulated to yield a dosage of, e.g., from about 0.1mg to 2 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mgdaily, or about 250 mg to 1 g daily. An alternative exemplary dose is inthe range of about from about 0.1 mg/kg to 1 g/kg, or about 0.1 mg/kg to5 mg/kg, or about 0.1 mg/kg to 1 mg/kg, or about 0.1 mg/kg to 0.6 mg/kg.Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid, or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil, such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

For parenteral use, including intravenous, intramuscular,intraperitoneal, intranasal, or subcutaneous routes, the agents of theinvention may be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms may be presented in unit-dose formsuch as ampoules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Illustrative infusion doses range from about 1 to 1000μg/kg/minute of agent admixed with a pharmaceutical carrier over aperiod ranging from several minutes to several days.

For nasal, inhaled, or oral administration, the inventive pharmaceuticalcompositions may be administered using, for example, a spray formulationalso containing a suitable carrier. The inventive compositions may beformulated for rectal administration as a suppository.

For topical applications, the compounds of the present invention arepreferably formulated as creams or ointments or a similar vehiclesuitable for topical administration. For topical administration, theinventive compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle. Anothermode of administering the agents of the invention may utilize a patchformulation to affect transdermal delivery.

Dosing and Administration

In some embodiments of the methods and compositions described herein, atherapeutically effective amount of one or more compounds that inhibitsFAK, SRC, and/or JAK2 in combination with a therapeutically effectiveamount of tametinib is administered to a host animal, such as a humanpatient, in need of treatment for cancer. In some embodiments of themethods and compositions described herein, a therapeutically effectiveamount of a compound that inhibits FAK, SRC, and JAK2 in combinationwith a therapeutically effective amount of trametinib is administered toa host animal, such as a human patient, in need of treatment for cancer.

As used herein, the term “therapeutically effective amount” refers tothat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a patient, which includesalleviation of the symptoms of the disease or disorder being treated. Inone aspect, the therapeutically effective amount is that which may treator alleviate the disease or symptoms. The specifictherapeutically-effective dose level for any particular patient willdepend upon a variety of factors, including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, gender and diet of the patient: the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidentally with the specific compound employed; andlike factors.

In some embodiments, a therapeutically effective amount of thecombination can be a synergistic combination that provides an enhancedresponse to treatment with the combination when compared to when the oneor more compounds that inhibits FAK, SRC, and/or JAK2 and trametinib areadministered individually. In some embodiments, the synergistic effectprovided by the administration of a therapeutically effective amount ofthe combination of the one or more compounds that inhibits FAK, SRC,and/or JAK2 and trametinib is a dose response that is more than additivecompared to the response of the each of the components of thecombination administered individually.

In some embodiments, an exemplary dose for each compound or agentindividually in the various methods and compositions described herein isin the range of about from about 0.1 mg to about 3 g, or about 0.5 mg toabout 2.5 mg, or about 1 mg to about 50 mg, or about 50 to about 250 mg,or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about2 g, or about 500 mg to about 1 g. It will be appreciated that allpossible subranges within the dose ranges described above arecontemplated and described herein. For example, a dose range of about150 to about 500 mg for a compound that inhibits FAK, SRC, and JAK2provided in the methods and compositions described herein includes dosesof about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg,about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg,about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg,about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg,about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg,about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg,about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg,about 500 mg, including all possible doses and ranges as may be requiredbased on such factors for determining a therapeutically effective amountas described herein. In some embodiments, the compound that inhibitsFAK, SRC, and JAK2, in particular Compound 1, provided in the methodsand compositions described herein can be dosed at about 40 mg, about 80mg, about ‘120 mg, or about 160 mg.

In some embodiments, trametinib can be administered in an amount of fromabout 0.3 mg daily to about 2.5 mg daily, or about 0.5 mg to about 2.5mg, or about 1 mg to about 2 mg. In some embodiments, trametinib can beadministered in an amount of about 0.5 mg, or about 2.0 mg.

In some embodiments, an exemplary dose for each compound or agentindividually in the various methods and compositions described herein isin the range of about from about 0.1 mg to about 3 g daily, or about 1mg to about 50 mg daily, or about 50 to about 250 mg daily, or about 150to about 500 mg daily, or about 150 to about 250 mg daily, or about 250mg to about 1 g daily, or about 100 mg to about 2 g daily, or about 500mg to about 2 g daily, or about 500 mg to about 1 g daily. It will beappreciated that all possible subranges within the daily dose rangesdescribed above are contemplated and described herein. For example, adose range of about 150 to about 500 mg daily for a compound thatinhibits FAK, SRC, and JAK2 provided in the methods and compositionsdescribed herein includes doses of about 150 mg daily, about 160 mgdaily, about 170 mg daily, about 180 mg daily, about 190 mg daily, about200 mg daily, about 210 mg daily, about 220 mg daily, about 230 mgdaily, about 240 mg daily, and about 250 mg daily, about 260 mg daily,about 270 mg daily, about 280 mg daily, about 290 mg daily, about 300 mgdaily, about 310 mg daily, about 320 mg daily, about 330 mg daily, about340 mg daily, about 350 mg daily, about 360 mg daily, about 370 mgdaily, about 380 mg daily, about 390 mg daily, about 400 mg daily, about410 mg daily, about 420 mg daily, about 430 mg daily, about 440 mgdaily, about 450 mg daily, about 460 mg daily, about 470 mg daily, about480 mg daily, about 490 mg daily, about 500 mg daily, including allpossible doses and ranges as may be required based on such factors fordetermining a therapeutically effective amount as described herein. Insome embodiments, the compound that inhibits FAK, SRC, and JAK2, inparticular Compound 1, provided in the methods and compositionsdescribed herein can be dosed at about 40 mg daily, about 80 mg daily,about ‘120 mg daily, or about 160 mg daily.

In some embodiments, trametinib can be administered in an amount of fromabout 0.3 mg daily to about 2.5 mg daily, or about 0.5 mg daily to about2.5 mg daily, or about 1 mg daily to about 2 mg daily. In someembodiments, trametinib can be administered in an amount of about 0.5 mgdaily, or about 2.0 mg daily.

In some embodiments, an alternative exemplary dose for each compound oragent individually in the various methods and compositions describedherein is in the range of about from about 0.001 mg/kg to about 1 g/kg,or about 0.05 mg/kg to about 50 mg/kg, or about 0.05 mg/kg to about 25mg/kg, or about 1.0 mg/kg to about 10 mg/kg, or about 1.0 mg/kg to about5 mg/kg, or about 0.1 mg/kg to about 5 mg/kg, or about 0.1 mg/kg toabout 1 mg/kg, or about 0.1 mg/kg to about 0.6 mg/kg. It will beappreciated that all possible subranges within the dose ranges describedabove are contemplated and described herein. For example, a dose rangeof about 1.0 mg/kg to about 10 mg/kg for a compound that inhibits FAK,SRC, and JAK2, in particular Compound 1, provided in the methods andcompositions described herein includes doses of about 1.0 mg/kg, about2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg, and about 10.0mg/kg, including all possible doses and ranges as may be required basedon such factors for determining a therapeutically effective amount asdescribed herein.

In some embodiments, a MEK inhibitor such as trametinib can beadministered in an amount of from about 0.004 mg/kg to about 0.2 mg/kg,or about 0.006 mg/kg to about 0.1 mg/kg.

In some embodiments, an alternative exemplary dose for each compound oragent individually in the various methods and compositions describedherein is in the range of about from about 0.1 mg/kg to about 1 g/kgdaily, or about 0.5 mg/kg to about 50 mg/kg daily, or about 0.5 mg/kg toabout 25 mg/kg daily, or about 1.0 mg/kg to about 10 mg/kg daily, orabout 1.0 mg/kg to about 5 mg/kg daily, or about 0.1 mg/kg to about 5mg/kg daily, or about 0.1 mg/kg to about 1 mg/kg daily, or about 0.1mg/kg to about 0.6 mg/kg daily. It will be appreciated that all possiblesubranges within the dose ranges described above are contemplated anddescribed herein. For example, a dose range of about 1.0 mg/kg to about10 mg/kg daily for a compound that inhibits FAK, SRC, and JAK2, inparticular Compound 1, provided in the methods and compositionsdescribed herein includes doses of about 1.0 mg/kg daily, about 2.0mg/kg daily, about 3.0 mg/kg daily, about 4.0 mg/kg daily, about 5.0mg/kg daily, about 6.0 mg/kg daily, about 7.0 mg/kg daily, about 8.0mg/kg daily, about 9.0 mg/kg daily, and about 10.0 mg/kg daily,including all possible doses and ranges as may be required based on suchfactors for determining a therapeutically effective amount as describedherein.

In some embodiments, a MEK inhibitor such as trametinib can beadministered in an amount of from about 0.004 mg/kg daily to about 0.2mg/kg daily, or about 0.006 mg/kg daily to about 0.1 mg/kg daily.

It will be appreciated that various dosing schedules for administrationof each compound or agent administered individually (or together) can beapplied to the methods and compositions described herein. It will befurther appreciated that a dosing schedule for each compound or agentadministered individually (or together) in the various methods andcompositions described herein can be defined by cycles of the dosingschedule, where such cycles are defined by the number of days oftreatment, number of doses of each compound or agent individually (ortogether), the total dose of each compound or agent individually (ortogether), and the like. In some embodiments, a host animal, such as ahuman patient in need of treatment, can be administered each compound oragent administered individually (or together) for at least one cycle,for at least two cycles, for at least three cycles, for at least fourcycles, and the like. Alternatively, in some embodiments, a host animal,such as a human patient in need of treatment, can be administered eachcompound or agent administered individually (or together) for from 1 toabout 50 cycles, from 1 to about 25 cycles, from 1 to about 20 cycles,from 1 to about 10 cycles, and the like. It will be appreciate that, insome embodiments, a dosing schedule for each compound or agentadministered individually (or together) in the various methods andcompositions described herein can include a holiday period during whichno compound or agent is administered, and such holiday period can bemeasured in days. In some embodiments, a dosing schedule for eachcompound or agent administered individually (or together) in the variousmethods and compositions described herein can be defined by a number ofcycles as described herein, followed by a holiday period, followed byanother number of cycles as described herein.

In some embodiments, an exemplary dosing schedule for each compound oragent individually in the various methods and compositions describedherein can include administration of a single daily dose (QD) or divideddosage units (e.g., BID (twice daily), TID (three times daily), QID(four times daily)). In some embodiments, a dosing schedule for eachcompound or agent in the various methods and compositions describedherein can be the same, such as all compounds or agents in the variousmethods and compositions described herein are administered QD, BID, orthe like. In some embodiments, a dosing schedule for each compound oragent in the various methods and compositions described herein can bedifferent from each other, such as one compound or agent in the variousmethods and compositions described herein is administered QD, andanother compound or agent in the various methods and compositionsdescribed herein is administered BID. In some embodiments, a dosingschedule for each compound or agent in the various methods andcompositions described herein can vary within a cycle, such as onecompound or agent in the various methods and compositions describedherein administered QD for a set number of days (e.g. QD for 1 day, 2days, 3 days, 4 days, etc) followed by BID for a set number of days(e.g. BID for 1 day, 2 days, 3 days, 4 days, etc). In some embodiments,a dosing schedule for each compound or agent in the various methods andcompositions described herein can be the same or different within acycle, such as one compound or agent in the various methods andcompositions described herein administered QD for a set number of days(e.g. QD for 1 day, 2 days, 3 days, 4 days, etc) followed by BID for aset number of days (e.g. BID for 1 day, 2 days, 3 days, 4 days, etc) tomatch the length of the cycle, and another compound or agentadministered BID for a set number of days to match the length of thecycle.

In some embodiments, the compound that inhibits FAK, SRC, and JAK2, inparticular Compound 1, and a MEK inhibitor such as trametinib areadministered at the same time. In some embodiments, the compound thatinhibits FAK, SRC, and JAK2, in particular Compound 1, and a MEKinhibitor such as trametinib are individually formulated, andadministered at the same time. In some embodiments, the compound thatinhibits FAK, SRC, and JAK2, in particular Compound 1, and trametinibare individually formulated, and administered in sequence. In someembodiments, the sequential administration of the compound that inhibitsFAK, SRC, and JAK2, in particular Compound 1, and a MEK inhibitor suchas trametinib can be accomplished with the compound that inhibits FAK,SRC and JAK2, in particular Compound 1, administered first (e.g. in themorning), and trametinib administered second (e.g. in the afternoon orevening). In some embodiments, the sequential administration of thecompound that inhibits FAK, SRC, and JAK2, in particular Compound 1, anda MEK inhibitor such as trametinib can be accomplished with trametinibadministered first (e.g. in the morning), and the compound that inhibitsFAK, SRC, and JAK2, in particular Compound 1, administered second (e.g.in the afternoon or evening).

In some embodiments, an exemplary dosing schedule for each compound oragent individually in the various methods and compositions describedherein can include administration of a compound that inhibits FAK, SRC,and JAK2, in particular Compound 1, at a dose level of from about 100 mgto about 300 mg QD for at least one day followed by a dose level of fromabout 100 mg to about 300 mg BID and trametinib at a dose level of fromabout 0.5 mg to about 2.5 mg QD. In some embodiments, the administrationof a compound that inhibits FAK, SRC, and JAK2, in particular Compound1, and trametinib on the dose schedule described above can be given forfrom 1 to about 20 cycles, where each cycle is from about 5 to about 20days. In some embodiments, the administration of a compound thatinhibits FAK, SRC, and JAK2, in particular Compound 1, and trametinib onthe dose schedule described above can be given for a set number of days,such as from about 20 to about 200 days, perpetually, or until treatmentis stopped by a treating physician.

EXAMPLES

Chemicals and Reagents

Compound 1 was prepared according to the methods described inWO2015/112806, see specifically Example 90 as described therein.WO2015/112806 is incorporated herein by reference for the preparation ofCompounds 1.

Trametinib was purchased from MedChemExpress. Drugs were prepared indimethyl sulfoxide (DMSO) at a concentration of 10-100 mmol/L stocksolutions and stored at −20° C. Further dilutions were made in culturemedium to final concentration before use. Phospho-STAT3 (Tyr705),phospho-AKT (Ser473), phospho-ERK1/2 (Thr202/Tyr204), phospho-FAK(Tyr576/577), STAT3, FAK, SRC, AKT, ERK, PARP, cleaved caspase-3,tubulin, and actin were purchased from Cell Signaling Technology(Beverly, Mass.).

Cell Lines

Human NSCLC cell lines H358, H23, H2122, H1373 and H1792, harboring KRASG12C mutation, were purchased from the American Type Culture Collection(ATCC). Human NSCLC cell line H441 with KRAS G12V mutation and H460 withKRAS Q61H mutation were also purchased from ATCC. The cell linesdescribed above were maintained in RPMI (Roswell Park Memorial Institutemedium) 1640 supplemented with 1% penicillin/streptomycin/glutamine(Gibco) and 10% fetal bovine serum (FBS) (Gibco) in 5% CO₂, 37° C. cellculture incubator. The human CRC cell line HCT-116 with KRAS G13D waspurchased from ATCC and maintained in DMEM supplemented with 1%penicillin/streptomycin/and 10% FBS (Gibco) in 5% CO₂, 37° C. cellculture incubator. The human pancreatic cell line PSN1 with KRAS G12Rwas purchased from ATCC and maintained in RPMI 1640 supplemented with 1%penicillin/streptomycin/and 10% FBS (Gibco) in 5% CO₂, 37° C. cellculture incubator. All cell lines were routinely evaluated forMycoplasma contamination.

Subcutaneous Xenograft Models in Immune Compromised Mice

Female athymic nude mice (5-8 weeks of age) were obtained from CharlesRiver Laboratory and were housed in Innovive IVC disposable cages onHEPA filtered ventilated racks with ad libitum access to rodent chow andwater. About five million cells in 100 μL serum-free medium supplementedwith 50% matrigel (Corning, Inc) were implanted subcutaneously in theright flank region of the mouse. Tumor size and body weight weremeasured on designated days.

Tumor size was measured with an electronic caliper and tumor volume wascalculated as the product of length*width²*0.5. Mice were randomized bytumor size into treatment groups when tumor volume reached about 200mm³. Compound 1 was administered orally twice a day at determined dosesand trametinib was administered orally once a day at determined doses.

Tumor Processing and Immunoblotting for In Vivo Pharmacodynamic Studies

Mice bearing xenograft tumors were humanely euthanized and tumors wereresected and snap frozen in liquid nitrogen and stored at −80° C. Frozentumor samples were processed at 4° C. in RIPA buffer to extractproteins. Protein concentration of the lysate was determined by RapidGold BCA Protein Assay (Life Technologies, Inc.) and lysate were dilutedto ensure the same protein concentration across samples. SDS loadingsamples were prepared by adding one volume of 4× LDS Sample Buffer (LifeTechnologies, Inc.) to three volumes of diluted protein lysate. TumorSDS protein samples were processed by SDS-PAGE and immunoblottedappropriate primary antibodies, followed by detection using HRPconjugated secondary antibodies. The signals from immunoblot weredetected by C-DiGit Blot Scanner from LI-COR using the Image StudioDigit software (LI-COR).

Example 1: NSCLC Cell Viability Assay

One to two thousand cells per well were seeded in 96 or 384 well whiteplate, and then treated with indicated compounds for 72-120 hours (37°C., 5% CO₂). Cell proliferation was measured using CellTiter-Gloluciferase-based ATP detection assay (Promega) following themanufactures's protocol. IC₅₀ determinations were performed usingGraphPad Prism software (GraphPad, Inc., San Diego, Calif.).

Results showing cell viability % of the MEK1/2 inhibitor (trametinib),Compound 1, and the combination of the MEK1/2 inhibitor (trametinib)with Compound 1 (1 μM) in mutant KRAS NSCLC cell lines are shown in FIG.1a-1x . The IC₅₀ values are summarized in Table 1. Although Calu-1,COR-L23, HCC1588, LCLC-97TM1, LU2512, NCI-H1155, NCI-H1373, NCI-H1573,SK-LU-1, and SW1573 NSCLC cell line endogenously expresses KRASmutations, the MEK inhibitor trametinib demonstrated weak-to-nodetectable inhibition of the cell proliferation. We investigated thesynergistic effect of Compound 1 (1 μM) in combination with trametinibon cell proliferation in NSCLC cell lines with a range of KRASmutations. Compound 1 alone had only weak inhibition activity in most ofthe tested NSCLC cell line with IC₅₀ ranges from 0.82 to 5 μM. A strongsynergy was observed with the combination of trametinib and Compound 1.Compound 1 at 1 μM concentration shifted trametinib's IC₅₀ from 100 nMto 3 nM against H358 cell proliferation. The combination shifted thetrametinib IC₅₀ to single digit IC₅₀ values in 18 of 24 mutant KRASNSCLC cell lines tested which encompassed the following KRAS mutations:G12C, G12D, G12S, G12V, G13D, Q61K, and Q61H.

TABLE 1 Trametinib + 1 μM Compound 1 Trametinib Compound 1 KRAS Celllines (IC₅₀ μM) (IC₅₀ μM) (IC₅₀ μM) Mutation A-427 0.83 0.06 <0.001 G12DA549 1.36 0.055 <0.001 G12S Calu-1 2.3 >10 0.01 G12C Calu-6 1.47 0.0120.001 Q61K COR-L23 2.2 0.164 0.001 G12V DV-90 7.27 0.014 0.004 G13DHCC1588 0.82 >10 <0.001 G12D LCLC-97TM1 0.93 0.344 <0.001 G12V LU25122.5 2.529 0.252 G12C NCI-H1155 NA >10 10 Q61H NCI-H1373 4.2 >10 0.007G12C NCI-H1573 NA >10 0.129 G12A NCI-H1792 1.32 0.051 <0.001 G12CNCI-H1944 2.62 >10 0.005 G13D NCI-H2009 2.28 >10 0.019 G12A NCI-H21221.16 0.01 <0.001 G12C NCI-H23 3.42 0.063 0.002 G12C NCI-H358 2.5 0.10.003 G12C NCI-H441 5.21 >10 0.001 G12V NCI-H460 1.22 0.07 <0.001 Q61HNCI-H727 4.53 0.003 <0.001 G12V SK-LU-1 0.95 >10 <0.001 G12D SW15732.59 >10 3.701 G12C SW900 2.08 0.074 0.005 G12V

Example 2. Apoptosis Assays

Two thousand cells per well were seeded in 384 well white plate, andthen treated with compounds for 24 or 48 hours (37° C., 5% CO₂). Cellcaspase-3/7 activity, a major hallmark of apoptosis, was measured usingCaspase-Glo® 3/7 detection assay (Promega) following the manufactures'sprotocol. Results showed the increase of caspase-3/7 activity with 24and 48 hour treatments of trametinib (50 nM), Compound 1 (1 μM), and thecombination of trametinib (50 nM) with Compound 1 (1 μM) in NSCLC celllines harboring a KRAS G12C mutation (H358, H2122), a KRAS Q61H mutation(Calu-6) and KRAS G12V mutation (H441) are shown in FIG. 1a-1d .Compound 1 alone causes modest increases in caspase-3/7 activity inNCI-H358, NCI-H2122 NSCLC cell lines after 48 hours of treatment (FIG.1a, 1c ). trametinib alone increased caspase-3/7 activity with H358,Calu-6, H2122 NSCLC cell lines after 48 hours of treatment (FIG. 1a-1c). The combination of Compound 1 with trametinib caused significantlymore caspase-3/7 activation compared to trametinib treatment alone forNSCLC cells with all tested mutant KRAS cell lines at both 24 and 48hour timepoints (FIG. 1a 1d).

Cleaved PARP and cleaved caspase-3 were evaluated as biomarkers ofapoptosis. Half a million cells per well were seeded in 24 well platefor 24 hrs, and then treated with compounds for 4, 24 or 48 hours. Cellswere collected after treatment and lysed in RIPA buffer (50 mM Tris, pH7.4, 150 mM NaCl, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS) supplementedwith 10 mM EDTA, 1× Halt protease and phosphatase inhibitors (ThermoScientific). Protein lysates (approximately 20 μg) was resolved on 4-12%Bolt Bis-Tris precasted gels with MES running buffer (LifeTechnologies), transferred to nitrocellulose membranes using Trans-BlotTurbo Transfer System (Bio-Rad) and detected with antibodies targetingPARP, Cleaved caspase-3, tubulin and actin (Cell Signaling Technology).Antibodies were typically incubated overnight at 4° C. with gentleshake, followed by washes and incubation with the appropriateHRP-conjugated secondary antibodies. Membranes were incubated withchemiluminescent substrate for 5 min at room temperature (SuperSignalWest Femto, Thermo Scientific). The chemiluminescent images wereacquired with a C-DiGit Imaging System (LI-COR Biosciences). Results inthe NCI-H358 and NCI-H2122 KRAS G12C NSCLC cell lines demonstratesignificant increases in cleaved PARP and cleaved caspase-3 after both24 hour and 48 hour treatments with the combination of trametinib (100nM) and Compound 1 (1 μM). Treatment with trametinib alone (100 nM) orCompound 1 alone (1 μM) resulted in small increases in cleaved PARP andcleaved caspase-3 Protein. Results in H2122 KRAS G12C NSCLC Demonstrateda Significant Increase in Cleaved PARP 24 hour treatment with Compound 1(1 μM).

Example 3. Immunoblotting for Cellular Kinase Phosphorylation Assays

Half a million cells per well were seeded in 24 well plate for 24 hrs,and then treated with compounds for 4, 24 or 48 hours. Cells werecollected after treatment and lysed in RIPA buffer (50 mM Tris, pH 7.4,150 mM NaCl, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS) supplemented with 10mM EDTA, 1× Halt protease and phosphatase inhibitors (ThermoScientific). Protein lysates (approximately 20 μg) was resolved on 4-12%Bolt Bis-Tris precasted gels with IVIES running buffer (LifeTechnologies), transferred to nitrocellulose membranes using Trans-BlotTurbo Transfer System (Bio-Rad) and detected with antibodies targetingphosphorylated STAT3, FAK, SRC, AKT, ERK, (Cell Signaling Technology),total STAT3, FAK, SRC, AKT, and ERK, (Cell Signaling Technology)Antibodies were typically incubated overnight at 4° C. with gentleshake, followed by washes and incubation with the appropriateHRP-conjugated secondary antibodies. Membranes were incubated withchemiluminescent substrate for 5 min at room temperature (SuperSignalWest Femto, Thermo Scientific). The chemiluminescent images wereacquired with a C-DiGit Imaging System (LI-COR Biosciences).

Results in Calu-6 KRAS Q61K NSCLC show that Compound 1 alone (1 μM)suppresses protein levels of phospho-AKT (pAKT), phospho-FAK (pFAK),phospho-SRC (pSRC), phospho-STAT3 (pSTAT3) at 4, 24 and 48 h timepoints. Trametinib treatment (50 μM) potently inhibited pERK but did notsuppress pAKT, pFAK, pSRC, or pSTAT3 protein levels at any time point.The combination of Compound 1 (1 μM) and trametinib (50 μM) potentlysuppresses pERK, pAKT, pFAK, pSRC, and pSTAT3 protein levels. Thecombination of suppression of these signaling nodes supports thesignificantly increased activation of apoptosis observed with thecombination treatment.

Further immunoblotting experiments showed that 1 μM Compound 1suppressed the induction of phosphorylated AKT by 50 nM trametinib inCalu-6 cells harboring a KRAS Q61K mutation.

Additionally, 1 μM Compound 1 more effectively suppressedtrametinib-induced phosphoAKT protein level compared to dasatinib (SRCinhibitor), defactinib (FAK inhibitor), or ruxolitinib (JAK1/2inhibitor) in Calu-6 cells harboring a KRAS Q61K mutation.

Further, Compound 1 demonstrated a dose-dependent response from 0 to3000 nM concentration for the inhibition of phosphorylation of AKT, ERK,FAK, STAT3 in NCI-H358 cells harboring a KRAS G12C mutation.

Example 4. Efficacy and Pharmacodynamic Modulation in Mouse TumorXenograft Models

Effect of Compound 1 in Combination with Trametinib in Calu-6Cell-Derived Xenograft Tumors

Calu-6 cells harboring a KRAS Q61K mutation. Athymic nude mice bearingCalu-6 cell-derived tumors were randomized to six groups and treatedwith vehicle BID, Compound 1 BID at 15 mg/kg, trametinib QD at 0.2mg/kg, Compound 1 BID at 15 mg/kg in combination with trametinib QD at0.2 mg/kg, trametinib QD at 0.6 mg/kg, and Compound 1 BID at 15 mg/kg incombination with trametinib QD at 0.6 mg/kg, respectively. The tumorvolume (TMV) vs time data are shown as mean±sem in FIG. 2a . At the datacut off on day 38 when the vehicle treated group was euthanized,treatment with Compound 1 in combination with trametinib at 0.2 mg/kgdose level significantly reduced tumor volume compared to the treatmentwith Compound 1 only or the treatment with trametinib (0.2 mg/kg) only(p<0.05, post hoc Dunnett's multiple comparison test following two-wayANOVA with six groups on day 31, 34, and 38). At the data cut off on day45, comparing the data from groups treated with Compound 1 BID at 15mg/kg, trametinib QD at 0.6 mg/kg, and Compound 1 BID at 15 mg/kg incombination with trametinib QD at 0.6 mg/kg revealed that the treatmentwith Compound 1 in combination with trametinib at 0.6 mg/kg dose levelsignificantly reduced tumor volume compared to the treatment withCompound 1 only or the treatment with trametinib (0.6 mg/kg) only(p<0.05, post hoc Dunnett's multiple comparison test following two-wayANOVA with three groups on day 42 and 45). Body weight of the mice weremeasured during treatment and are shown as mean±sem in FIG. 2b .Although the body weight change over time in the group mice treated withCompound 1 in combination with trametinib at 0.6 mg/kg dose level wassignificantly different from other groups, the body weights at the endof treatment were not significantly different from those at the baselinebefore treatment started (p>0.1, Wilcoxon matched-pairs signed ranktest), with the mean body weight slightly reduced to about 94% ofbaseline level following 35 days of treatment.

Pharmacodynamic Effect of Compound 1 in Combination with Trametinib inCalu-6 Cell-Derived Xenograft Tumors

To evaluate the pharmacodynamic effect of Compound 1 in combination withtrametinib in Calu-6 cell-derived xenograft tumors, tumor lysate wasprepared and analyzed by immunoblotting using antibodies against thecandidate molecules selected from signaling pathways that can bepotentially modified by Compound 1 and/or trametinib (FIG. 9). Theinhibitory activities of Compound 1 against SRC and FAK weredemonstrated by the reduction of phosphorylated SRC and FAK signals intumors treated with Compound 1 at 15 mg/kg twice a day (BID) either asthe single agent or in combination with trametinib at 0.6 mg/kg. Inaddition, Compound 1 in combination with trametinib reduced thephosphorylated ERK signal, a key pathway involved in cell proliferationand survival. Finally, phosphorylated EGFR appeared to be induced bytreatment of trametinib. Compound 1 treatment either in combination withtrametinib or as a single agent reduced the EGFR activity.

Example 5: CRC Cell Viability Assay

Two thousand cells per well were seeded in 96 or 384 well white plate,and then treated with indicated compounds for 72 hours (37° C., 5% CO₂).Cell proliferation was measured using CellTiter-Glo luciferase-based ATPdetection assay (Promega) following the manufacture's protocol. IC₅₀determinations were performed using GraphPad Prism software (GraphPad,Inc., San Diego, Calif.).

Results showing cell viability % of the MEK1/2 inhibitor (trametinib),Compound 1, and the combination of the MEK1/2 inhibitor (trametinib)with Compound 1 (1 μM) in mutant KRAS colorectal cancer (CRC) cell lineswere evaluated. The IC₅₀ values are summarized in Table 2.

TABLE 2 Trametinib + CRC mutant KRAS Compound 1 Trametinib Compound 1(1μM) KRAS cell lines (IC₅₀ μM) (IC₅₀ μM) (IC₅₀ μM) mutation DLD-1 1.371.39 0.119 G13D HCT-116 1.66 0.024 <0.001 G13D HCT-15 1.66 1.81 0.063G13D LoVo 3.07 0.006 0.000 G13D LS1034 3.85 0.013 0.004 A146T LS123 3.0610 0.053 G12S LS180 18.6 >10 0.053 G12D LS513 2.22 0.006 0.002 G12DNCI-H716 0.667 0.459 <0.001 R97I NCI-H747 1.94 0.011 0.001 G13D SK-CO-11.20 0.007 <0.001 G12V SNU-81 >10 0.069 0.039 A146T SNU-C2A 8.907 24.00.346 G12A SW1116 10.8 0.035 0.024 G12A SW480 2.87 0.013 0.001 G12VSW620 1.83 0.042 <0.001 G12V SW837 4.18 0.016 0.004 G12C SW948 2.180.144 0.014 Q61L T84 5.31 0.547 0.078 G13D

Example 6: Pancreatic Cancer Cell Viability Assay

Two thousand cells per well were seeded in 96 or 384 well white plate,and then treated with indicated compounds for 72 hours (37° C., 5% CO₂).Cell proliferation was measured using CellTiter-Glo luciferase-based ATPdetection assay (Promega) following the manufacturer's protocol. IC₅₀determinations were performed using GraphPad Prism software (GraphPad,Inc., San Diego, Calif.).

Results showing cell viability % of the MEK1/2 inhibitor (trametinib),Compound 1, and the combination of the MEK1/2 inhibitor (trametinib)with Compound 1 (1 μM) in mutant KRAS pancreatic cancer cell lines wereevaluated. The IC₅₀ values are summarized in Table 3.

TABLE 3 Trametinib + Pancreatic Compound 1 Cancer KRAS Compound 1Trametinib (1 μM) KRAS Cell lines IC50 (μM) IC50 (μM) IC50 (μM) mutationASPC-1 8.23 0.05 0.02 G12D Capan-1 1.04 0.03 <0.001 G12V Capan-2 0.690.08 <0.001 G12V CFPAC-1 2.38 NA 0.01 G12V HPAC 1.06 0.03 <0.001 G12DHPAF-II 3.53 0.04 0.02 G12D HS766T 2.49 0.01 <0.001 Q61H HUP-T4 2.21 NA0.05 G12V KP4 1.32 NA 0.06 G12D MIAPACA-2 1.13 0.02 <0.001 G12C Panc03.27 1.18 1.48 0.08 G12V Panc 05.04 1.02 0.02 <0.001 G12D Panc 10.052.77 0.30 0.06 G12D Panc-1 5.28 NA >10 G12V SU.86.86 2.01 NA 6.65 G12DSW1990 6.37 NA 0.23 G12D

Example 7. Cell Proliferation Assays of Compound 1 in Combination withTrametinib in A-427, HCT-116 and PSN1 Cell Models

Cell proliferation assays were performed in select cell models (A-427,HCT-116 and PSN1) in a combination dose matrix comprising a combinationof trametinib and Compound 1 to determine synergy at other dose levelsof Compound 1. One to two thousand cells per well were seeded in 96 wellclear bottom black-walled 96 well microplates, and then treated withindicated compounds for 72-120 hours (37° C., 5% CO₂). Trametinibconcentrations ranged from 10 to 1.5 nM titrated 3-fold across the plateand Compound 1 titrated from 3 μM to 37 nM titrated 3 fold down asindicated. Single agent efficacy from Trametinib and Compound 1 was alsotested at dose ranges of 10 μM to 1.5 nM titrated 3-fold across for bothcompounds. Cell proliferation was measured using CellTiter-Gloluciferase-based ATP detection assay (Promega) following themanufacturer's protocol and read with a SYNERGY H1 multi-reader(BIOTEK). IC50 determinations were performed using GraphPad Prismsoftware (GraphPad, Inc., San Diego, Calif.). Degree of synergy wasdetermined with the full combination matrix using a BLISS additivitysoftware (Bioinformatics, Volume 33, Issue 15, 1 Aug. 2017, Pages2413-2415).

7A. Trametinib and Compound 1 Combination Cell Viability Assay for A-427NSCLC

Trametinib treatment in combination with Compound 1 demonstrated a dosedependent benefit with addition of Compound 1 at differentconcentrations. Additional combinations at varying doses of bothtrametinib and Compound 1 revealed ranges of drug concentrations thatmay yield synergistic benefit. Synergy was assessed by BLISSindependence analysis on the Synergyfinder website (Ianevski A, He L,Aittokallio T, Tang J. SynergyFinder: a web application for analyzingdrug combination dose-response matrix data. Bioinformatics. 2017 Aug. 1;33(15):2413-2415). Concentrations that yielded greatest synergy fellbetween 13.7 to 123 nM for trametinib and 37 to 333 nM for Compound 1with an average calculated BLISS synergy score of 13.69.

TABLE 4 Drug Most Synergistic Combination Synergy Score Area ScoreMethod Compound 1 + 4.14 13.69 Bliss Trametinib

7B. Trametinib and Compound 1 Combination Cell Viability Assay forHCT-116 CRC

Trametinib treatment in combination with Compound 1 demonstrated a dosedependent benefit with addition of Compound 1 at differentconcentrations. Additional combinations at varying doses of bothtrametinib and Compound 1 revealed ranges of drug concentrations thatmay yield synergistic benefit. Synergy was assessed by BLISSindependence analysis on the Synergyfinder website. Concentrations thatyielded greatest synergy fell between 4.6 to 41.2 nM for trametinib and333 nM to 3 μM for Compound 1 with an average calculated BLISS synergyscore of 14.02.

TABLE 5 Drug Most Synergistic Combination Synergy Score Area ScoreMethod Compound 1 + 4.51 14.02 Bliss Trametinib

7C. Trametinib and Compound 1 Combination Cell Viability Assay for PSN1

Trametinib treatment in combination with Compound 1 demonstrated a dosedependent benefit with addition of Compound 1 at differentconcentrations. Additional combinations at varying doses of bothtrametinib and Compound 1 revealed ranges of drug concentrations thatmay yield synergistic benefit. Synergy was assessed by BLISSindependence analysis on the Synergyfinder. Concentrations that yieldedgreatest synergy fell between 1.5 to 13.7 nM for trametinib and 111 nMto 1 μM for Compound 1 with an average calculated BLISS synergy score of13.64.

TABLE 6 Drug Most Synergistic Combination Synergy Score Area ScoreMethod Compound 1 + 4.85 13.65 Bliss Trametinib

Example 8. Immunoblotting for Cellular Kinase Phosphorylation (HCT-116)

Approximately 300 thousand cells per well were seeded in 6 well platefor 24 hrs, and then treated with compounds for 4, 24 or 48 hours. Cellswere collected after treatment and lysed in RIPA buffer (50 mM Tris, pH7.4, 150 mM NaCl, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS) supplementedwith 10 mM EDTA, 1× Halt protease and phosphatase inhibitors (ThermoScientific). Protein lysates (approximately 20 μg) was resolved on 4-12%Bolt Bis-Tris precast gels with IVIES running buffer (LifeTechnologies), transferred to nitrocellulose membranes using Trans-BlotTurbo Transfer System (Bio-Rad) and detected with antibodies targetingphosphorylated STAT3, FAK, SRC, AKT, ERK, S6 (Cell SignalingTechnology), total STAT3, FAK, SRC, AKT, and ERK, S6, and beta-Actin(Cell Signaling Technology) Antibodies were typically incubatedovernight at 4° C. with gentle rocking, followed by washes andincubation with the appropriate HRP-conjugated secondary antibodies.Membranes were incubated with chemiluminescent substrate (Bio-RadClarity Western ECL) for 2 min at room temperature. The chemiluminescentimages were acquired with an iBRIGHT FL1500 Imaging System(ThermoFisher). Results in HCT-116 KRAS G13D CRC show that Compound 1alone suppresses protein levels of phospho-FAK (pFAK), phospho-SRC(pSRC), phospho-STAT3 (pSTAT3) at 4 and 24 h time points. Trametinibinhibited pERK at all timepoints and inhibited pSRC at 24h as a singleagent. Single agent trametinib upregulated pSTAT3, however, thisupregulation was repressed by addition of compound 1 as observed at 4and 24h. Both trametinib and compound 1 inhibited phosphorylation of theS6 protein as single agents, however, combination treatment of the twocompounds resulted in a more complete inhibition by 24h. The combinationof suppression of these signaling nodes supports the significantlyincreased inhibition of cell proliferation observed with the combinationtreatment. Combination of Compound 1 with trametinib also results ingreater PARP cleavage.

Example 9. Immunoblotting for Cellular Kinase Phosphorylation (PSN1)

Approximately half a million cells per well were seeded in 6 well platefor 24 hrs, and then treated with compounds for 4, 24 or 48 hours. Cellswere collected after treatment and lysed in RIPA buffer (50 mM Tris, pH7.4, 150 mM NaCl, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS) supplementedwith 10 mM EDTA, 1× Halt protease and phosphatase inhibitors (ThermoScientific). Protein lysates (approximately 20 μg) was resolved on 4-12%Bolt Bis-Tris precast gels with IVIES running buffer (LifeTechnologies), transferred to nitrocellulose membranes using Trans-BlotTurbo Transfer System (Bio-Rad) and detected with antibodies targetingphosphorylated AKT, ERK, S6 (Cell Signaling Technology), total AKT, andERK, S6, and beta-Actin (Cell Signaling Technology) Antibodies weretypically incubated overnight at 4° C. with gentle rocking, followed bywashes and incubation with the appropriate HRP-conjugated secondaryantibodies. Membranes were incubated with chemiluminescent substrate(Bio-Rad Clarity Western ECL) for 2 min at room temperature. Thechemiluminescent images were acquired with an iBRIGHT FL1500 ImagingSystem (ThermoFisher). Results in PSN1 KRAS G12R Pancreatic cancer cellline show that trametinib inhibited pERK as a single agent in and thatcombination with Compound 1 yielded similar results. Single agentCompound 1 at both 333 nM and 1 μM inhibited phosphorylation of AKT atS473. Furthermore, trametinib was able to inhibit phosphorylation of S6at S235/S236 as a single agent and addition of Compound 1 enhancedphosphoS6 inhibition.

Example 10. Effect of Compound 1 in Combination with Trametinib inHCT-116 Cell-Derived Xenograft Tumor Model of CRC

HCT-116 is a colon cancer cell line harboring a KRAS G13D mutation.SCID/Beige mice bearing HCT-116 cell-derived tumors were randomized totreatment groups, including groups treated with vehicle BID, Compound 1BID at 15 mg/kg, trametinib QD at 0.4 mg/kg, Compound 1 BID at 15 mg/kgin combination with trametinib QD at 0.4 mg/kg. The tumor volume (TMV)vs time data are shown as mean±sem in FIG. 4a . At the data cutoff onday 18 when the vehicle treated group was euthanized, treatment withCompound 1 in combination with trametinib at 0.4 mg/kg dose levelsignificantly reduced tumor volume compared to the treatment withCompound 1 only (p<0.0001, post hoc Dunnett's multiple comparison testfollowing two-way ANOVA) or the treatment with trametinib (0.4 mg/kg)only (p<0.001, post hoc Dunnett's multiple comparison test followingtwo-way ANOVA). Body weight of the mice were measured during treatmentand are shown as mean±sem in FIG. 4b . At the data cutoff on day 18 whenthe vehicle treated group was euthanized, there is no statisticallysignificant difference of body weight among treatment groups (p=0.61,two-way ANOVA).

Example 11. Pharmacodynamic Effect of Compound 1 in Combination withTrametinib in HCT-116 Cell-Derived Xenograft Tumors

To evaluate the pharmacodynamic effect of Compound 1 in combination withtrametinib in HCT-116 cell-derived xenograft tumors, tumor lysate wasprepared and analyzed by immunoblotting using antibodies against thecandidate molecules selected from signaling pathways that can bepotentially modified by Compound 1 and/or trametinib from tumor samplescollected at 2h or 9h post the last dose. The inhibitory activities ofCompound 1 against SRC were demonstrated by the reduction ofphosphorylated SRC signals in tumors treated with Compound 1 at 15 mg/kgtwice a day (BID) either as the single agent or in combination withtrametinib at 0.4 mg/kg at both time points, whereas reduction ofphosphorylated SRC was not observed in the trametinib treatment group.In addition, trametinib treatment led to elevated phosphorylated FAKlevel, while Compound 1 in combination with trametinib attenuated thiselevation at both time points. Compound 1 inhibited the phosphorylationof STAT3 at 2h but not 9h post the last dose. Finally, reduction ofphosphorylated ERK signal was observed in groups treated with trametinibeither as a single agent or in combination with Compound 1.

Example 12. Effect of Compound 1 in Combination with Trametinib in theSubcutaneous mLU6045 MuPrime Mouse Lung Cancer Model with KRAS^(G12D/+);p53^(−/−) Mutations

The subcutaneous mLU6045 MuPrime lung cancer model is derived from mouselung tumors induced by constitutive activate KRAS^(G12D/+) heterozygousmutation and p53 homozygous null mutation in lung cells. It is worthnoting that the drug effect was evaluated in C57BL/6 mice with an intactimmune system in this study. The tumor volume vs time data are shown asmean±sem in FIG. 5a . Tumor volume in the group treated with Compound 1in combination with trametinib was statistically significantly smallerthan those in the group treated with vehicle (p<0.0001, mixed-effectsmodel followed by Tukey's multiple comparison test) or Compound 1 only(p=0.0052, mixed-effects model followed by Tukey's multiple comparisontest) and have a trend to be smaller than that in the group treated withtrametinib only (p=0.0590, mixed-effects model followed by Tukey'smultiple comparison test). Further analysis of data on the last day ofstudy (day 23) showed that tumor volume of the group treated withCompound 1 in combination with trametinib was statisticallysignificantly smaller than that of the vehicle treated group (p<0.0001,two-stage linear step-up procedure of Benjamini, Krieger and Yekutielifollowing Kruskal-Wallis test), or that of the Compound 1 treated group(p=0.0123, two-stage linear step-up procedure of Benjamini, Krieger andYekutieli following Kruskal-Wallis test), or that of the trametinibtreated group (p=0.0188, two-stage linear step-up procedure ofBenjamini, Krieger and Yekutieli following Kruskal-Wallis test). Theseresults suggest a promising combination effect of Compound 1 andtrametinib on anti-tumor activity in this mouse lung cancer modelharboring the KRAS^(G12D/+); p53^(−/−) mutations with an intact immunesystem. The body weight vs time data are shown as mean±sem in FIG. 5b .Although slight and gradual body weight loss was observed in the groupof mice treated with Compound 1 in combination with trametinib and onemouse was found dead on day 22, body weight of the group treated withCompound 1 in combination with trametinib was not statisticallydifferent from that of the group treated with vehicle (p=0.2231, groupeffect of the mixed-effect model).

Example 13: Cell Viability Assays Testing Compound 1 in Combination withTrametinib, SHP099/TNO155, LY3214996, RO5126766/CH5126766, orSelumetinib in Patient Derived Lung Organoid and Spheroid Models

Human patient derived tumor cells obtained from patient biopsies weremaintained and expanded in xenograft mice hosts. Subsequently, patientderived tumors were harvested at appropriate tumor size and dissociatedwith dipase enzyme to smaller organoids ranging between 20 to 100micrometer in size. Processed tumor organoids were combined withMatrigel, plated onto 384 well plates and treated with compounds atindicated final drug concentrations as single agent and in combinationwith select concentrations of Compound 1. Organoids were cultured for 5days at 37° C. with 5% CO₂. On day 5, cell viability was indirectlymeasured with 3D CTG (Cell Titer Glo) luciferase-based ATP detectionassay (Promega) following manufacture's protocol and luminescence isread with an Envision multi-reader.

In parallel, ex vivo 3D Spheroids are isolated from patient derivedxenograft (PDX) tumors maintained in mice: tumors are harvested atappropriate tumor size and dissociated with collagenase at 37° C. for upto 30 to 60 mins. Spheroid cell isolates are counted and combined withmethylcellulose (final concentration of 0.65%). Approximately 15,000tumor cell isolates in 90 ul of suspension growth medium are seeded perwell in 96-well plates. On the next day after seeding, cells are treatedwith compounds at indicated final drug concentrations as single agentand in combination with select concentrations of Compound 1. Compoundtreated tumor cell isolates were cultured for 6 days at 37° C. with 5%CO₂ during which time, isolates are allowed to form anchorageindependent tumor clusters called spheroids. On day 7, cell viability ofspheroids was indirectly measured with 3D CTG (Cell Titer Glo)luciferase-based ATP detection assay (Promega) following manufacture'sprotocol and luminescence is read with an Envision multi-reader. IC₅₀and area under the curve (AUC) values were calculated using GraphPadPrism software (GraphPad, Inc., San Diego, Calif.).

Results showing cell viability % of the MAPK pathway inhibitors,Compound 1, and the combination of the various inhibitors with Compound1 (1 μM) in patient derived mutant KRAS lung organoid or spheroid modelsare summarized in Table 7.

TABLE 7 combination combination single with 1 uM single with 1 uMPatient Derived Test agent Compound 1 agent Compound 1 Organoid modelcompounds IC50 (nM) IC50 (nM) AUC AUC LU5178B Trametinib 94 3 199 74KRAS G12D Selumetinib >10000 23 676 312 LY3214996 >10000 812 725 389(ERKi) RO5126766 1387 27 401 172 (RAF/MEKi) TNO155 >100000 4221 76993823 (SHP099) Repotrectinib 8699 634 LU5162B Trametinib >10000 <1.5 598334 KRAS G12D Selumetinib >10000 1 824 336 LY3214996 >10000 <1.5 758 345(ERKi) RO5126766 3370 1 486 249 (RAF/MEKi) TNO155 >100000 2 7699 2769(SHP099) Repotrectinib 898 292 LU0876ex Trametinib 11 <1.5 29.4 20.5KRAS G12D Selumetinib 198 <1.5 318 176 LY3214996 353 23 206 135 (ERKi)RO5126766 162 <1.5 214 113 (RAF/MEKi) TNO155 2743 <1.5 3778 1733(SHP099) Repotrectinib 879 243 LU11548ex Trametinib 24 5 165 103 KRASG12V Selumetinib 2221 297 445 303 LY3214996 788 238 326 201 (ERKi)RO5126766 1212 122 361 277 (RAF/MEKi) TNO155 >100000 62624 8003 5834(SHP099) Repotrectinib 3166 445 LU6419ex Trametinib 22 5 230 127 KRASG12V Selumetinib 5502 2283 576 497 LY3214996 9752 1987 659 408 (ERKi)RO5126766 1651 744 437 352 (RAF/MEKi) TNO155 62863 57950 7499 6403(SHP099) Repotrectinib >10000 712

Example 14. Cell Viability Assays Testing Compound 1 in Combination withTrametinib, RO5126766/C115126766, or Mirdametinib in Patient DerivedPancreatic Cancer Organoid Models

Human patient derived tumor cells obtained from patient biopsies weremaintained and expanded in xenograft mice hosts. Subsequently, patientderived tumors were harvested at appropriate tumor size and dissociatedwith dipase enzyme to smaller organoids ranging between 20 to 100micrometer in size. Processed tumor organoids were combined withMatrigel, plated onto 384 well plates and treated with compounds atindicated final drug concentrations as single agent and in combinationwith select concentrations of Compound 1. Organoids were cultured for 5days at 37° C. with 5% CO₂. On day 5, cell viability was indirectlymeasured with 3D CTG (Cell Titer Glo) luciferase-based ATP detectionassay (Promega) following manufacture's protocol and luminescence isread with an Envision multi-reader. IC₅₀ and area under the curve (AUC)values were calculated using GraphPad Prism software (GraphPad, Inc.,San Diego, Calif.).

Results showing cell viability % of the various MAPK pathway inhibitors,Compound 1, and the combination of the various inhibitors with Compound1 (1 μM or 0.5 μM as indicated) in patient derived mutant KRAS lungorganoid or spheroid models are summarized in Tables 8 and 9.

TABLE 8 combination combination single with 1 uM single with 1 uM agentCompound 1 Pancreatic Test agent Compound 1 Viability Viability CancerOrganoid compounds IC50 (nM) IC50 (nM) AUC AUC PA13004B Trametinib 23<1.5 390 121 KRAS-G12R RO5126766 >10000 <1.5 592 213 (RAF/MEKi)Repotrectinib 544 204 PA20066B Trametinib 4 <1.5 203 72 KRAS-G12VRO5126766 61 <1.5 365 163 (RAF/MEKi) Repotrectinib 636 198 PA20067BTrametinib 8 <1.5 366 154 KRAS-G12V RO5126766 >10000 <1.5 531 300(RAF/MEKi) Repotrectinib 881 269 PA20076B Trametinib 4 <1.5 263 123KRAS-G12D RO5126766 >10000 <1.5 508 221 (RAF/MEKi) Repotrectinib 733 205PA20077B Trametinib 6 6 229 68 KRAS-G12D RO5126766 >10000 373 577 402(RAF/MEKi) Repotrectinib 5005 581

TABLE 9 combination combination single with 0.5 uM single with 0.5 uMagent Compound 1 Pancreatic Test agent Compound 1 Viability ViabilityCancer Organoid compounds IC50 (nM) IC50 (nM) AUC AUC PA20074BTrametinib 8 1 448 238 KRAS-G12R Mirdametinib 446 9 448 284 RO51267661527 32 481 369 (RAF/MEKi) Repotrectinib 873 342 PA20068B Trametinib 162 259 187 KRAS-G12V Mirdametinib 575 53 326 217 RO5126766 1443 140 458315 (RAF/MEKi) Repotrectinib 1356 373 PA20069B Trametinib 3 1 201 115KRAS-G12D Mirdametinib 60 30 237 162 RO5126766 286 60 352 254 (RAF/MEKi)Repotrectinib 1443 391

1. A method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 having structure

or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a MEK inhibitor.
 2. The method of claim 1, wherein at least one genetically altered oncogenic gene has been previously identified in the patient, wherein the at least one genetically altered oncogenic gene is a genetically altered KRAS, a genetically altered NRAS, a genetically altered HRAS, a genetically altered BRAF, a genetically altered MEK, and/or a genetically altered PI3K.
 3. The method of claim 2, wherein the genetically altered KRAS comprises at least one mutation selected from the group consisting of G12C, G12V, G12D, G12A, G13C, G12S, D12R, D12F, G13D, G13V, G13R, G13E, Q61H, Q61E, Q61L, and Q61R; or selected from the group consisting of G12D, G13D, and Q61H; or KRAS comprises at least one mutation that is not G12A, G12C, G12S, G12V, and Q61K.
 4. The method of claim 1, wherein the cancer is colorectal cancer or pancreatic cancer.
 5. The method of claim 1, wherein the compound that inhibits FAK, SRC, and JAK2 is administered in an amount of from about 40 mg to about 200 mg.
 6. The method of claim 1, wherein the MEK inhibitor is administered in an amount of from about 0.5 mg to about 2.5 mg.
 7. The method claim 1, wherein the MEK inhibitor is trametinib, selumetinib, LY3214996, RO5126766, TNO155 (SHP099), or mirdametinib, or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1, wherein the MEK inhibitor is trametinib, or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1, wherein the compound that inhibits FAK, SRC and JAK2 is administered in an amount of about 40 mg, about 80 mg, about 120 mg, or about 160 mg by once a day or twice a day.
 10. The method of claim 1, wherein the MEK inhibitor is administered in an amount of about 1 mg or about 2 mg.
 11. The method of claim 1, wherein the compound that inhibits FAK, SRC and JAK2 is administered on a schedule of at least one dose of about 40 mg, about 80 mg QD, about 120 mg QD, or about 160 mg QD, followed by at least one dose of about 40 mg BID, about 80 mg BID, about 120 mg BID, or about 160 mg BID.
 12. The method of claim 1, wherein the MEK inhibitor is administered in at least one dose of about 1 mg QD, or about 2 mg QD.
 13. The method of claim 1, wherein the compound that inhibits FAK, SRC and JAK2 is administered at the same time as the MEK inhibitor.
 14. The method of claim 1, wherein the compound that inhibits FAK, SRC and JAK2 is administered prior to the MEK inhibitor.
 15. The method of claim 1, wherein the compound that inhibits FAK, SRC and JAK2 is administered after the MEK inhibitor.
 16. The method of claim 1, wherein the patient has not received a prior treatment.
 17. The method of claim 1, wherein the patient has received at least one prior treatment of one or more chemotherapeutic agents or immunotherapies.
 18. The method of claim 1, wherein the patient has received at least one prior treatment of one or more chemotherapeutic agents or immunotherapies, and has developed an acquired resistance to the treatment, and/or developed bypass resistance to the treatment. 